Process of preparing esters and ethers of probucol and derivatives thereof

ABSTRACT

A probucol or a probucol derivative can be efficiently converted to a monoester or monoether of probucol by reacting the free hydroxyl-containing probucol or a derivative thereof (by which is meant a probucol compound with at least one substituent that is different from that on the parent probucol molecule but which maintains the two free hydroxyl groups) with a Grignard reagent or a lithium reagent that produces a magnesium bromide or lithium salt of probucol or the probucol derivative. The probucol compound anion is then reacted with an ester or ether forming compound.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/757,664, filed Jan. 13, 2004, now U.S. Pat. No. 7,273,948, whichclaims priority to U.S. Provisional Application Ser. No. 60/439,665,filed Jan. 13, 2003.

FIELD OF THE INVENTION

The present invention is a process for the manufacture of esters andethers of probucol and derivatives thereof that are suitable for thetreatment of inflammatory and cardiovascular diseases.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,262,439 to Parthasarathy, which is assigned toAtheroGenics, Inc. discloses analogs of probucol with increased watersolubility in which one or both of the hydroxyl groups are replaced withester groups that increase the water solubility of the compound. The'439 patent reports that carboxylic acid derivatives of probucol can beprepared by treating probucol with an excess of dicarboxylic acidanhydride and catalytic amounts of 4-dimethyl-aminopyridine at atemperature sufficient to ensure that the dicarboxylic acid anhydride isliquid. Under these conditions, no anhydrous solvent is necessary, asthe anhydride itself acts as a solvent.

WO 01/70757 filed by AtheroGenics, Inc. describes the use of certaincompounds of the following formula, and pharmaceutically acceptablesalts thereof along with method of use and methods of manufacturing:

wherein

-   -   a) R_(a), R_(b), R_(c), and R_(d) are independently any group        that does not adversely affect the desired properties of the        molecule, including hydrogen, alkyl, substituted alkyl, aryl,        substituted aryl, heteroaryl, substituted heteroaryl, alkaryl,        substituted alkaryl, aralkyl, or substituted aralkyl; and    -   b) Z is (i) a substituted or unsubstituted carbohydrate, (ii) a        substituted or unsubstituted alditol, (iii) C₁₋₁₀alkyl or        substituted C₁₋₁₀alkyl, terminated by sulfonic acid, (iv)        C₁₋₁₀alkyl or substituted C₁₋₁₀alkyl, terminated by phosphonic        acid, (v) substituted or unsubstituted        C₁₋₁₀alkyl-O—C(O)—C₁₋₁₀alkyl, (vi) straight chained        polyhydroxylated C₃₋₁₀ alkyl; (vii) —(CR₂)₁₋₆—COOH, wherein R is        independently hydrogen, halo, amino, or hydroxy, and wherein at        least one of the R substituents is not hydrogen; or (viii)        —(CR₂)₁₋₆—X, wherein X is aryl, heteroaryl, or heterocycle, and        R is independently hydrogen, halo, amino, or hydroxy.

U.S. Pat. No. 6,147,250, assigned to AtheroGenics, Inc., providescompounds, compositions, method for inhibiting the expression of VCAM-1,and methods of preparing said compounds and compositions. The patentreports that a monoester can be prepared by treating a quantity ofprobucol in a 0.1 M solution of tetrahydrofuran with 2 equivalents ofsodium hydride and stirred at room temperature for 30 minutes. To thereaction mixture is added 3 equivalents of an acid chloride or acidanhydride and the reaction stirred at room temperature for 16 hours. Thereaction is quenched with 1 N HCl and diluted with ethyl acetate. Theaqueous layer is removed and the ethyl acetate layer is washed withwater and then with an aqueous saturated sodium chloride solution. Theethyl acetate solution is dried over magnesium sulfate, gravity orvacuum filtered, and then concentrated. The product is purified bysilica gel chromatography yielding 14% of the desired compound.

U.S. Pat. No. 6,323,359 discloses and claims methods of manufacturing agroup of compounds found in the '250 patent. The '359 patent disclosesthe use of alkali metal hydroxide, alkali metal alkoxide, alkaliammonium alkoxide, alkyl ammonium hydroxide to form alkali metal saltsof probucol compounds and then reacting the salts with dicarboxylic acidanhydride.

French Patent Publication No. 2.168.137 describes the production ofdiesters of probucol by reacting probucol with a halide or anhydride ofan organic acid in an inert solvent with heat and in the presence of abase such as an alkaline hydroxide or carbonate, a tertiary amine or atertiary nitrogenous heterocycle. The O-metallic derivative of probucolcan also be used as the reaction intermediate.

What is still needed is a method of manufacturing a group of compoundsdescribed in U.S. Pat. Nos. 6,141,250; 6,323,359; 5,262,439; and WO01/70757 that is efficient and gives good yields.

It is another object of the invention to provide a process for thepreparation of monoesters and monoethers of probucol or a probucolderivative that optimizes the amount of final product.

It is yet another object of the present invention to provide a processfor the preparation of monoesters and monoethers of probucol or aprobucol derivative that minimizes the amount of reagent used.

SUMMARY OF THE INVENTION

A process for the preparation of esters and ethers of probucol or aprobucol derivative is provided that optimizes the amount of monoesterin the final product mixture and minimizes the amount of reagents.

It has been discovered that probucol or a derivative thereof can beefficiently converted to esters of probucol by reacting a freehydroxyl-containing probucol or a derivative thereof (by which is meanta probucol compound with at least one substituent that is different fromthat on the parent probucol molecule but which maintains the two freehydroxyl groups) with a Grignard reagent or a lithium reagent thatproduces a magnesium salt or lithium salt of probucol or the probucolderivative, respectively. The probucol compound salt with strong oxideanion is then reacted with an ester forming compound such as a saturatedor unsaturated acyl halide, saturated or unsaturated carboxylic acidanhydride, a saturated or unsaturated activated carboxylic acid ester orother ester-forming reagent. The probucol compound salt canalternatively be reacted with an ether forming compound to generate aprobucol ether or probucol ether derivative.

In a broad description, the invention consists of processes tomanufacturing a compound of Formula I and salts thereof

wherein R¹, R², R³, and R⁴ are independently selected from the groupconsisting of hydrogen and alkyl, said alkyl optionally substituted byhydroxy, alkyl, alkenyl, acyl, nitro, amino, halo, carboxy and cyano;R⁵ and R⁶ are the same or different and independently selected from thegroup consisting of alkyl, alkenyl, and aryl all of which can beoptionally substituted by hydroxy, alkyl, alkenyl, acyl, nitro, amino,halo, carboxy and cyano;R⁵ and R⁶ can come together to form a carbocyclic ring;X is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated acyl, and an optionally substituted saturatedacyl, said optionally substituted unsaturated acyl and optionallysubstituted saturated acyl optionally containing a polar or chargedfunctionality;Y is selected from the group consisting of an optionally substitutedunsaturated acyl and an optionally substituted saturated acyl, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula II

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined, with aGrignard Reagent to form a magnesium salt or a reagent selected from thegroup consisting of alkyl lithium, alkenyl lithium, alkynyl lithium,aryl lithium, aralkyl lithium, and a heteroaryl lithium, all which canbe optionally substituted, to form a lithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated acyl halide,saturated or unsaturated carboxylic acid anhydride and a saturated orunsaturated activated carboxylic acid ester, all of which may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, amino,halo, protected carboxy and cyano;separating and isolating said compound of Formula I or salts thereof; orX is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated alkyl, and an optionally substituted saturatedalkyl, said optionally substituted unsaturated alkyl and optionallysubstituted saturated alkyl optionally containing a polar or chargedfunctionality;Y is selected from the group consisting of an optionally substitutedunsaturated alkyl, and an optionally substituted saturated alkyl, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula II wherein R¹, R², R³, R⁴, R⁵ and R⁶ areas previously defined, with a Grignard Reagent to form a magnesium saltor a reagent selected from the group consisting of alkyl lithium,alkenyl lithium, alkynyl lithium, aryl lithium, aralkyl lithium, and aheteroaryl lithium, all which can be optionally substituted, to form alithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated alkyl halide,saturated or unsaturated alkyl-O-sulfonyl alkyl, a saturated orunsaturated alkyl-O-sulfonyl aryl, a saturated or unsaturatedalkyl-O-acyl, and a saturated or unsaturated epoxide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, amino, halo, protected carboxy, epoxide and cyano;separating and isolating said compound of Formula I or salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

A process for the preparation of an ester of probucol or a probucolderivative is provided that optimizes the amount of final product andminimizes the amount of reagents used.

Probucol or a probucol derivative thereof can be converted to amonoester of probucol or probucol derivative by reacting the probucol orprobucol derivative thereof with a Grignard reagent or a lithium reagentthat produces a magnesium salt or lithium salt of probucol or theprobucol derivative, respectively. The resulting probucol salt is thenreacted with an ester forming compound such as a saturated orunsaturated acyl halide, saturated or unsaturated carboxylic acidanhydride, a saturated or unsaturated activated carboxylic acid ester orother ester-forming reagent, all of which may be optionally substituted.

Product ratios of about 64% monoester (wherein 66% monoester constitutesthe expected theoretical yield), about 13% diester and about 23%unreacted probucol or probucol derivative can be achieved by theoptimized selection of reaction conditions.

In another embodiment, the invention provides a process for thepreparation of an ether of probucol or a probucol derivative thatoptimizes the amount of the final product and minimizes the amount ofreagents used.

Probucol or a probucol derivative can be converted to a monoether ofprobucol or probucol derivative by reacting the probucol or probucolderivative thereof with a Grignard reagent or a lithium reagent thatproduces a magnesium salt or lithium salt of probucol or the probucolderivative, respectively. The resulting probucol salt is then reactedwith an ether forming compound such as an alkyl halide, alkyl tosylate,alkyl mesylate, other alkyl group with an appropriate leaving group orother ether-forming reagent, all of which may be optionally substituted.

Any solvent can be used that achieves the desired results. Examples ofsolvents include any organic solvent that is inert under the reactionconditions, aprotic solvents, ethers (such as THF or ethyl ether),liquid amides (such as DMF), hydrocarbons (including aromatichydrocarbons such as toluene) and mixtures thereof. The word solvent asused herein includes mixtures of solvents. Solubilizing reagents as usedherein include but are not limited to tetramethylurea;1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone andhexamethylphosphoramide. Generally, alcohols or other reagents thatcould react with a Grignard reagent or lithium reagent should beavoided.

Typically the reaction is carried out in an inert atmosphere such asunder a nitrogen or argon blanket.

In the first step of the reaction, probucol or a probucol derivative ismixed with a Grignard reagent or lithium reagent in the presence of asolvent, co-solvent or solubilizing reagent or mixtures thereof to forma probucol salt.

In the second step, the probucol salt is reacted with the ester or etherforming agent. The probucol salt of the first step can be isolated andused in the second step at a later time or both the first and secondsteps can take place in a single reaction vessel by simply introducingthe ester or ether forming reagent either neat or in a suitable solventto the probucol salt mixture. Alternatively, the probucol salt mixturecan be added to a reaction vessel that contains the ester or etherforming agent either neat or in an appropriate solvent.

The first and second steps can be carried out at the same or differenttemperatures, or both or either can be reacted under gradienttemperatures. Both steps generally are carried out at any temperature(s)that achieve the desired results.

The reactions are maintained at low temperature, including anytemperature to about or just above the freezing point of the solvent. Inother embodiments, the temperature of either or both of the reactionsrange from below 0° C. to room temperature or higher, including up tothe boiling point of the solvent. The selection of temperature candepend on the preference of the operator, the available equipment, thefreezing and boiling points of the solvent or solvents used, thereactivity of the reagents, and the control of side reactions.

Alternatively, the natural exotherm of either or both of the reactionsare used to warm the reaction and to avoid the need for externalapplication of heat. Excessive or undesired exotherms may be controlledwith external cooling.

In another aspect of the invention, a Grignard reagent or a lithiumreagent is added to a mixture containing probucol or a probucolderivative and an ester or ether forming agent in a solvent, co-solvent,or solubilizing agent or mixtures thereof.

In a particularly broad form, the invention encompasses methods ofmanufacturing compounds of Formula I or salts thereof

wherein R¹, R², R³, and R⁴ are independently selected from the groupconsisting of hydrogen and alkyl, said alkyl optionally substituted byhydroxy, alkyl, alkenyl, acyl, nitro, amino, halo, carboxy and cyano;R⁵ and R⁶ are the same or different and independently selected from thegroup consisting of alkyl, alkenyl, and aryl all of which can beoptionally substituted by hydroxy, alkyl, alkenyl, acyl, nitro, amino,halo, carboxy and cyano;R⁵ and R⁶ can come together to form a carbocyclic ring;X is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated acyl, and an optionally substituted saturatedacyl, said optionally substituted unsaturated acyl and optionallysubstituted saturated acyl optionally containing a polar or chargedfunctionality;Y is selected from the group consisting of an optionally substitutedunsaturated acyl and an optionally substituted saturated acyl, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula II

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined, with aGrignard Reagent to form a magnesium salt or a reagent selected from thegroup consisting of alkyl lithium, alkenyl lithium, alkynyl lithium,aryl lithium, aralkyl lithium, and a heteroaryl lithium, all which canbe optionally substituted, to form a lithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated acyl halide,saturated or unsaturated carboxylic acid anhydride and a saturated orunsaturated activated carboxylic acid ester, all of which may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, amino,halo, protected carboxy and cyano;separating and isolating said compound of Formula I or salts thereof, orX is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated alkyl, and an optionally substituted saturatedalkyl, said optionally substituted unsaturated alkyl and optionallysubstituted saturated alkyl optionally containing a polar or chargedfunctionality;Y is selected from the group consisting of an optionally substitutedunsaturated alkyl, and an optionally substituted saturated alkyl, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula II wherein R¹, R², R³, R⁴, R⁵ and R⁶ areas previously defined, with a Grignard Reagent to form a magnesium saltor a reagent selected from the group consisting of alkyl lithium,alkenyl lithium, alkynyl lithium, aryl lithium, aralkyl lithium, and aheteroaryl lithium, all which can be optionally substituted, to form alithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated alkyl halide,saturated or unsaturated alkyl-O-sulfonyl alkyl, a saturated orunsaturated alkyl-O-sulfonyl aryl, a saturated or unsaturatedalkyl-O-acyl, and a saturated or unsaturated epoxide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, amino, halo, protected carboxy, epoxide and cyano;separating and isolating said compound of Formula I or salts thereof.

In a 1^(st) narrowed embodiment, the invention encompasses processes ofmanufacturing compounds of Formula I or salts thereof

wherein R¹, R², R³, and R⁴ are the same or different and independentlyselected from the group consisting of hydrogen and an alkyl having from1 to 6 carbon atoms;R⁵ and R⁶ are the same or different and independently selected from thegroup consisting of an alkyl having from 1 to 8 carbon atoms, an alkenylhaving from 2 to 8 carbon atoms, and aryl;R⁵ and R⁶ can come together to form a carbocyclic ring containing from 3to 8 carbon atoms;X is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated acyl having from 1 to 18 carbon atoms, and anoptionally substituted saturated acyl having from 1 to 18 carbon atoms,said optionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula II

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined, with aGrignard Reagent to form a magnesium salt or a reagent selected from thegroup consisting of an alkyl lithium, alkenyl lithium, alkynyl lithium,aryl lithium, aralkyl lithium, and a heteroaryl lithium, all which canbe optionally substituted to form a lithium salt; reacting saidmagnesium salt or lithium salt with a compound selected from the groupconsisting of a saturated or unsaturated acyl halide, saturated orunsaturated carboxylic acid anhydride and a saturated or unsaturatedactivated carboxylic acid ester, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, amino,halo, protected carboxy and cyano;separating and isolating said compound of Formula I or salts thereof, orX is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated alkyl having from 1 to 10 carbon atoms, and anoptionally substituted saturated alkyl having from 1 to 10 carbon atoms,said optionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula II wherein R¹, R², R³, R⁴, R⁵ and R⁶ areas previously defined, with a Grignard Reagent to form a magnesium saltor a reagent selected from the group consisting of an alkyl lithium,alkenyl lithium, alkynyl lithium, aryl lithium, aralkyl lithium, and aheteroaryl lithium, all which can be optionally substituted to form alithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated alkyl halide,saturated or unsaturated alkyl-O-sulfonyl alkyl, a saturated orunsaturated alkyl-O-sulfonyl aryl, a saturated or unsaturatedalkyl-O-acyl, and a saturated or unsaturated epoxide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, halo, protected carboxy, epoxide and cyano; separating andisolating said compound of Formula I or salts thereof.

In a 2nd embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof

wherein:X is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated acyl having from 1 to 18 carbon atoms, and anoptionally substituted saturated acyl having from 1 to 18 carbon atoms,said optionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV

with a Grignard Reagent to form a magnesium salt or a reagent selectedfrom the group consisting of an alkyl lithium, alkenyl lithium, alkynyllithium, aryl lithium, aralkyl lithium, and a heteroaryl lithium, allwhich can be optionally substituted to form a lithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated acyl halide,saturated or unsaturated carboxylic acid anhydride and a saturated orunsaturated activated carboxylic acid ester, all of which may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, amino,halo, protected carboxy and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 3rd embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent to form amagnesium salt or a reagent selected from the group consisting of analkyl lithium, alkenyl lithium, alkynyl lithium, aryl lithium, aralkyllithium, and a heteroaryl lithium, all which can be optionallysubstituted to form a lithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated acyl halide,saturated or unsaturated carboxylic acid anhydride and a saturated orunsaturated activated carboxylic acid ester, all of which may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 4^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated acyl having from 1 to 18 carbon atoms, and anoptionally substituted saturated acyl having from 1 to 18 carbon atoms,said optionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent to form amagnesium salt; reacting said magnesium salt with a compound selectedfrom the group consisting of a saturated or unsaturated acyl halide,saturated or unsaturated carboxylic acid anhydride and a saturated orunsaturated activated carboxylic acid ester, all of which may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy and cyano; separating and isolating said compound ofFormula III or salts thereof.

In a 5^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent to form amagnesium salt; reacting said magnesium salt with a compound selectedfrom the group consisting of a saturated or unsaturated acyl halide,saturated or unsaturated carboxylic acid anhydride and a saturated orunsaturated activated carboxylic acid ester, all of which may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy and cyano; separating and isolating said compound ofFormula III or salts thereof.

In a 6^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of alkylmagnesium halide, alkenylmagnesium halide,alkynylmagnesium halide, arylmagnesium halide, arylalkylmagnesiumhalide, alkylmagnesium alkyl, arylmagnesium aryl, arylalkynylmagnesiumhalide, arylalkenylmagnesium halide, and heteroarylmagnesium halide, allof which may optionally be substituted by one or more selected from thegroup consisting of protected hydroxy, alkyl, alkenyl, protected acyl,nitro, protected amino, halo and protected carboxy, to form a magnesiumsalt; reacting said magnesium salt with a compound selected from thegroup consisting of a saturated or unsaturated carboxylic acidanhydride, all of which may optionally be substituted by one or moreselected from the group consisting of protected hydroxy, alkyl, alkenyl,acyl, nitro, protected amino, halo, protected carboxy and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 7^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV

with a Grignard Reagent selected from the group consisting ofalkylmagnesium halide, alkenylmagnesium halide, alkynylmagnesium halide,all of which may optionally be substituted by one or more selected fromthe group consisting of protected hydroxy, alkyl, alkenyl, protectedacyl, nitro, protected amino, halo and protected carboxy, to form amagnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In an 8^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of Methylmagnesium bromide;Octadecylmagnesium chloride; Tetradecylmagnesium chloride;n-Pentadecylmagnesium bromide; Ethynylmagnesium chloride;n-Nonylmagnesium bromide; n-Octylmagnesium chloride;(2-Methylpropenyl)magnesium bromide; Cyclopentylmagnesium bromide;tert-Pentyl magnesium chloride; Cyclopropylmagnesium bromide;(1-Methyl-2-propenyl)magnesium chloride; 1-Decylmagnesium bromide;1-Octylmagnesium bromide; 1-Propynylmagnesium bromide; Dodecylmagnesiumbromide; sec-Butylmagnesium chloride; 1-Propenylmagnesium bromide;Isopropenylmagnesium bromide; (2,2-Dimethylpropyl)magnesium chloride;1-Heptylmagnesium bromide; 3-Butenylmagnesium bromide; 1-Pentylmagnesiumchloride; 2-Methylpropylmagnesium chloride;(2-Methyl-2-propenyl)magnesium chloride; Ethynylmagnesium bromide;1-Hexylmagnesium bromide; Vinylmagnesium chloride; Allylmagnesiumchloride; Ethylmagnesium chloride; n-Propylmagnesium chloride;Vinylmagnesium bromide; Allylmagnesium bromide; Isopropylmagnesiumchloride; Isopropylmagnesium bromide; Cyclohexylmagnesium chloride;Cyclohexylmagnesium bromide; 1-Propylmagnesium bromide;Isobutylmagnesium bromide; Ethylmagnesium bromide; 2-Butylmagnesiumbromide; 2-Propylmagnesium bromide; Methylmagnesium iodide;n-Butylmagnesium chloride; n-Butylmagnesium bromide; tert-Butylmagnesiumchloride; and Methylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 9^(th) embodiment, the invention is represented by the process ofthe 8^(th) embodiment wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of Methylmagnesium bromide;Octadecylmagnesium chloride; Tetradecylmagnesium chloride;n-Nonylmagnesium bromide; n-Octylmagnesium chloride;(2-Methylpropenyl)magnesium bromide; Cyclopentylmagnesium bromide;tert-Pentyl magnesium chloride; Cyclopropylmagnesium bromide;1-Decylmagnesium bromide; 1-Octylmagnesium bromide; Dodecylmagnesiumbromide; sec-Butylmagnesium chloride; (2,2-Dimethylpropyl)magnesiumchloride; 1-Heptylmagnesium bromide; 1-Pentylmagnesium chloride;2-Methylpropylmagnesium chloride; 1-Hexylmagnesium bromide;Ethylmagnesium chloride; n-Propylmagnesium chloride; Isopropylmagnesiumchloride; Isopropylmagnesium bromide; Cyclohexylmagnesium chloride;Cyclohexylmagnesium bromide; 1-Propylmagnesium bromide;Isobutylmagnesium bromide; Ethylmagnesium bromide; 2-Butylmagnesiumbromide; 2-Propylmagnesium bromide; Methylmagnesium iodide;n-Butylmagnesium chloride; n-Butylmagnesium bromide; tert-Butylmagnesiumchloride; and Methylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 10^(th) embodiment, the invention is represented by the process ofthe 9^(th) embodiment

wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of Methylmagnesium bromide;n-Octylmagnesium chloride; (2-Methylpropenyl)magnesium bromide;Cyclopentylmagnesium bromide; tert-Pentyl magnesium chloride;Cyclopropylmagnesium bromide; 1-Octylmagnesium bromide;sec-Butylmagnesium chloride; (2,2-Dimethylpropyl)magnesium chloride;1-Heptylmagnesium bromide; 1-Pentylmagnesium chloride;2-Methylpropylmagnesium chloride; 1-Hexylmagnesium bromide;Ethylmagnesium chloride; n-Propylmagnesium chloride; Isopropylmagnesiumchloride; Isopropylmagnesium bromide; Cyclohexylmagnesium chloride;Cyclohexylmagnesium bromide; 1-Propylmagnesium bromide;Isobutylmagnesium bromide; Ethylmagnesium bromide; 2-Butylmagnesiumbromide; 2-Propylmagnesium bromide; Methylmagnesium iodide;n-Butylmagnesium chloride; n-Butylmagnesium bromide; tert-Butylmagnesiumchloride; and Methylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In an 11^(th) embodiment, the invention is represented by the process ofthe 10^(th) embodiment wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of n-Octylmagnesium chloride;(2-Methylpropenyl)magnesium bromide; Ethylmagnesium chloride;n-Propylmagnesium chloride; Isopropylmagnesium chloride;Isopropylmagnesium bromide; Cyclohexylmagnesium chloride;Methylmagnesium iodide; n-Butylmagnesium chloride; tert-Butylmagnesiumchloride; and Methylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 12^(th) embodiment, the invention is represented by the process ofthe 11^(th) embodiment wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with isopropylmagnesiumchloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 13^(th) embodiment, the invention is represented by the process ofthe 12^(th) embodiment wherein:

X is hydrogen;

Y is a saturated acyl having from 1 to 10 carbon atoms or an optionallysubstituted saturated acyl having from 1 to 10 carbon atoms, saidsaturated acyl and optionally substituted saturated acyl optionallycontaining a polar or charged functionality; comprising:reacting a solution of a compound of Formula IV with isopropylmagnesiumchloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano;separating and isolating said compound of Formula III or salts thereof.

In a 14^(th) embodiment, the invention is represented by the process ofthe 13^(th) embodiment to manufacture a compound of Formula V or saltsthereof

comprising:reacting a solution of a compound of Formula IV with isopropylmagnesiumchloride to form a magnesium salt;reacting said magnesium salt with succinic acid anhydride; separatingand isolating said compound of Formula V or salts thereof.

In a 15^(th) embodiment, the invention is represented by the process ofthe 13^(th) embodiment to manufacture a compound of Formula VI or saltsthereof

comprising:reacting a compound of Formula IV with isopropylmagnesium chloride toform a magnesium salt;reacting said magnesium salt with glutaric acid anhydride;separating and isolating said compound of Formula VI or salts thereof.

In a 16^(th) embodiment, the invention is represented by the process ofthe 13^(th) embodiment to manufacture a compound of Formula VII or saltsthereof

comprising:reacting a compound of Formula IV with isopropylmagnesium chloride toform a magnesium salt;reacting said magnesium salt with acetic acid anhydride;separating and isolating said compound of Formula VII or salts thereof.

In a 17^(th) embodiment, the invention is represented by the process ofthe 13^(th) embodiment to manufacture a compound of Formula VIII orsalts thereof

wherein R⁷ and R⁸ are independently selected from the group consistingof hydrogen, acyl, alkyl, alkenyl, aryl, aralkyl, Si(alkyl)₃, protectedcarboxy, alksulfonyl, and arylsulfonylcomprising:reacting a compound of Formula IV with isopropylmagnesium chloride toform a magnesium salt;reacting said magnesium salt with acetic acid anhydride substituted by aprotected or unprotected amino;separating and isolating said compound of Formula VIII or salts thereof

In an 18^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from arylmagnesium halide or heteroarylmagnesium halide to forma magnesium salt, wherein said arylmagnesium halide andheteroarylmagnesium halide may optionally be substituted by one or moreselected from the group consisting of protected hydroxy, alkyl, alkenyl,protected acyl, nitro, protected amino, halo and protected carboxy;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 19^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Chloro-4-fluorophenylmagnesium bromide;3-Fluoro-2-methylphenylmagnesium bromide;5-Fluoro-2-methoxyphenylmagnesium bromide;5-Fluoro-2-methylphenylmagnesium bromide;3,5-Dimethyl-4-methoxyphenylmagnesium bromide;3-Fluoro-4-methylphenylmagnesium bromide;3-[Bis(trimethylsilyl)amino]phenylmagnesium chloride; 3-Thienylmagnesiumiodide; 3-Fluoro-4-chlorophenylmagnesium bromide;3,4,5-Trifluorophenylmagnesium bromide;4-Methoxy-2-methylphenylmagnesium bromide; 2,4-Dimethoxyphenylmagnesiumbromide; 2,3-Dimethylphenylmagnesium bromide; 3-Methylphenylmagnesiumchloride; (4-methyl-1-naphthalenyl)magnesium bromide;(3-fluoro-4-methoxyphenyl)magnesium bromide; 2-Chloro-5-thienylmagnesiumbromide; 3,4-Dimethylphenylmagnesium chloride;3-Methyl-2-thienylmagnesium bromide; Pentamethylphenylmagnesium bromide;3,4-Dimethoxyphenylmagnesium bromide; (3,4-Dimethylphenyl)magnesiumbromide; (3,5-Dichlorophenyl)magnesium bromide;(4-Fluoro-3-methylphenyl)magnesium bromide; 3,4-Dichlorophenylmagnesiumbromide; 2,3,5,6-Tetramethylphenylmagnesium bromide; 9-Phenanthrylmagnesium bromide; (4-tert-Butylphenyl)magnesium bromide;2,5-Dimethoxyphenylmagnesium bromide; 3,5-Difluorophenylmagnesiumbromide; 4-Chlorophenylmagnesium chloride;(6-Methoxy-2-naphthyl)magnesium bromide; (2-Methoxy-1-naphthyl)magnesiumbromide; 3-Methoxyphenylmagnesium bromide; (3-Chlorophenyl)magnesiumbromide; (3,5-Dimethylphenyl)magnesium bromide;(2-Methylphenyl)magnesium chloride; 4-Fluoro-2-methylphenylmagnesiumbromide; (2,5-Dimethylphenyl)magnesium bromide; m-Methylphenylmagnesiumbromide; 4-Ethylphenylmagnesium bromide; 2-Pyridylmagnesium bromide;4-Phenoxyphenylmagnesium bromide; 2-Naphthylmagnesium bromide;(2-Methyl-1-naphthyl)magnesium bromide; 2,6-Dimethylphenylmagnesiumbromide; 2-Ethylphenylmagnesium bromide; 4-(Methylthio)phenylmagnesiumbromide; (4-Isopropylphenyl)magnesium bromide;3,4-Methylenedioxyphenylmagnesium bromide; 3-Fluorophenylmagnesiumbromide; (o-Methoxyphenyl)magnesium bromide; Phenylmagnesium iodide;(4-Methoxyphenyl)magnesium bromide; 4-(Dimethylamino)phenylmagnesiumbromide; 2-Thienylmagnesium bromide; (4-Methylphenyl)magnesium bromide;Mesitymagnesium bromide; 2-Tolylmagnesium bromide;Pentafluorophenylmagnesium bromide; (4-Chlorophenyl)magnesium bromide;1-Naphthalenylmagnesium bromide; 4-Methylphenylmagnesium chloride;4-Fluorophenylmagnesium bromide; Phenylmagnesium chloride;Phenylmagnesium bromide; and (4-Biphenylyl)magnesium bromide to form amagnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 20^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3,5-Dimethyl-4-methoxyphenylmagnesium bromide;4-Methoxy-2-methylphenylmagnesium bromide; 2,4-Dimethoxyphenylmagnesiumbromide; 2,3-Dimethylphenylmagnesium bromide; 3-Methylphenylmagnesiumchloride; 3,4-Dimethylphenylmagnesium chloride;Pentamethylphenylmagnesium bromide; 3,4-Dimethoxyphenylmagnesiumbromide; (3,4-Dimethylphenyl)magnesium bromide;2,3,5,6-Tetramethylphenylmagnesium bromide;(4-tert-Butylphenyl)magnesium bromide; 2,5-Dimethoxyphenylmagnesiumbromide; 3-Methoxyphenylmagnesium bromide; (3,5-Dimethylphenyl)magnesiumbromide; (2-Methylphenyl)magnesium chloride;(2,5-Dimethylphenyl)magnesium bromide; m-Methylphenylmagnesium bromide;4-Ethylphenylmagnesium bromide; 4-Phenoxyphenylmagnesium bromide;2,6-Dimethylphenylmagnesium bromide; 2-Ethylphenylmagnesium bromide;(4-Isopropylphenyl)magnesium bromide; 3,4-Methylenedioxyphenylmagnesiumbromide; (o-Methoxyphenyl)magnesium bromide; Phenylmagnesium iodide;(4-Methoxyphenyl)magnesium bromide; (4-Methylphenyl)magnesium bromide;Mesitymagnesium bromide; 2-Tolylmagnesium bromide;4-Methylphenylmagnesium chloride; Phenylmagnesium chloride; andPhenylmagnesium bromide to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 21^(st) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methylphenylmagnesium chloride;(4-tert-Butylphenyl)magnesium bromide; 3-Methoxyphenylmagnesium bromide;(2-Methylphenyl)magnesium chloride; m-Methylphenylmagnesium bromide;4-Ethylphenylmagnesium bromide; 2-Ethylphenylmagnesium bromide;(4-Isopropylphenyl)magnesium bromide; (o-Methoxyphenyl)magnesiumbromide; Phenylmagnesium iodide; (4-Methoxyphenyl)magnesium bromide;(4-Methylphenyl)magnesium bromide; 2-Tolylmagnesium bromide;4-Methylphenylmagnesium chloride; Phenylmagnesium chloride; andPhenylmagnesium bromide to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 22^(nd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methylphenylmagnesium chloride;3-Methoxyphenylmagnesium bromide; (2-Methylphenyl)magnesium chloride;m-Methylphenylmagnesium bromide; (o-Methoxyphenyl)magnesium bromide;Phenylmagnesium iodide; (4-Methoxyphenyl)magnesium bromide;(4-Methylphenyl)magnesium bromide; 2-Tolylmagnesium bromide;4-Methylphenylmagnesium chloride; Phenylmagnesium chloride; andPhenylmagnesium bromide to form a magnesium salt; reacting saidmagnesium salt with a compound selected from the group consisting ofsuccinic acid anhydride, glutaric acid anhydride, adipic acid anhydride,suberic acid anhydride, sebacic acid anhydride, azelaic acid anhydride,phthalic acid anhydride, maleic acid anhydride, and acetic acidanhydride, all of which may optionally be substituted by one or moreselected from the group consisting of protected hydroxy, alkyl, alkenyl,acyl, nitro, protected amino, halo, protected carboxy and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 23^(rd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 24^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is a saturated acyl having from 1 to 10 carbon atoms or an optionallysubstituted saturated acyl having from 1 to 10 carbon atoms, saidsaturated acyl and optionally substituted saturated acyl optionallycontaining a polar or charged functionality; comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano;separating and isolating said compound of Formula III or salts thereof.

In a 25^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula V or salts thereof

comprising:reacting a solution of a compound of Formula IV

with a Grignard Reagent selected from the group consisting of3-Methoxyphenylmagnesium bromide; (o-Methoxyphenyl)magnesium bromide;and Phenylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with succinic acid anhydride;separating and isolating said compound of Formula V or salts thereof.

In a 26^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula VI or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with glutaric acid anhydride;separating and isolating said compound of Formula VI or salts thereof.

In a 27^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula VII or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with acetic acid anhydride;separating and isolating said compound of Formula VII or salts thereof.

In a 28th embodiment, the invention is represented by the process tomanufacture a compound of Formula VIII or salts thereof

wherein R⁷ and R⁸ are independently selected from the group consistingof hydrogen, acyl, alkyl, alkenyl, aryl, aralkyl, Si(alkyl)₃, protectedcarboxy, alksulfonyl, and arylsulfonyl;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with acetic acid anhydride substituted by aprotected or unprotected amino;separating and isolating said compound of Formula VIII or salts thereof

In a 29^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof

wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of arylalkylmagnesium halide, arylalkynylmagnesiumhalide, and arylalkenylmagnesium halide to form a magnesium salt, all ofwhich may optionally be substituted by one or more selected from thegroup consisting of protected hydroxy, alkyl, alkenyl, protected acyl,nitro, protected amino, halo and protected carboxy; reacting saidmagnesium salt with a compound selected from the group consisting ofsuccinic acid anhydride, glutaric acid anhydride, adipic acid anhydride,suberic acid anhydride, sebacic acid anhydride, azelaic acid anhydride,phthalic acid anhydride, maleic acid anhydride, and acetic acidanhydride, all of which may optionally be substituted by one or moreselected from the group consisting of protected hydroxy, alkyl, alkenyl,acyl, nitro, protected amino, halo, protected carboxy and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 30^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 2,5-Dimethylbenzylmagnesium chloride;2,6-Dichlorobenzylmagnesium chloride; 2,4-Dichlorobenzylmagnesiumchloride; 2-Fluorobenzylmagnesium chloride; 2,4-Dimethylbenzylmagnesiumchloride; 3-Bromobenzylmagnesium bromide; 4-Bromobenzylmagnesiumbromide; (2-Phenylethyl)magnesium chloride; 3-Fluorobenzylmagnesiumchloride; (3,4-Dichlorobenzyl)magnesium chloride; 2-Bromobenzylmagnesiumbromide; 4-Methoxybenzylmagnesium chloride; 4-Methylbenzylmagnesiumchloride; m-Methylbenzylmagnesium chloride; 2-Methylbenzylmagnesiumchloride; 3-Chlorobenzylmagnesium chloride; 2-Chlorobenzylmagnesiumchloride; m-Methoxybenzylmagnesium chloride; Benzylmagnesium chloride;(Phenylethynyl)magnesium bromide; 4-Fluorobenzylmagnesium chloride;Benzylmagnesium bromide; 4-Chlorobenzylmagnesium chloride; and2-Chloro-6-fluorobenzylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 31^(st) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 2,5-Dimethylbenzylmagnesium chloride;2,4-Dimethylbenzylmagnesium chloride; (2-Phenylethyl)magnesium chloride;4-Methoxybenzylmagnesium chloride; 4-Methylbenzylmagnesium chloride;m-Methylbenzylmagnesium chloride; 2-Methylbenzylmagnesium chloride;m-Methoxybenzylmagnesium chloride; Benzylmagnesium chloride; andBenzylmagnesium bromide to form a magnesium salt; reacting saidmagnesium salt with a compound selected from the group consisting ofsuccinic acid anhydride, glutaric acid anhydride, adipic acid anhydride,suberic acid anhydride, sebacic acid anhydride, azelaic acid anhydride,phthalic acid anhydride, maleic acid anhydride, and acetic acidanhydride, all of which may optionally be substituted by one or moreselected from the group consisting of protected hydroxy, alkyl, alkenyl,acyl, nitro, protected amino, halo, protected carboxy and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 32^(nd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with Benzylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 33^(rd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is a saturated acyl having from 1 to 10 carbon atoms or an optionallysubstituted saturated acyl having from 1 to 10 carbon atoms, saidsaturated acyl and optionally substituted saturated acyl optionallycontaining a polar or charged functionality; comprising:reacting a solution of a compound of Formula IV with Benzylmagnesiumchloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano;separating and isolating said compound of Formula III or salts thereof.

In a 34^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula V or salts thereof

comprising:reacting a compound of Formula IV with Benzylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with succinic acid anhydride;separating and isolating said compound of Formula V or salts thereof.

In a 35^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula VI or salts thereof

comprising:reacting a compound of Formula IV with Benzylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with glutaric acid anhydride;separating and isolating said compound of Formula VI or salts thereof.

In a 36^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula VII or salts thereof

comprising:reacting a compound of Formula IV with Benzylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with acetic acid anhydride;separating and isolating said compound of Formula VII or salts thereof.

In a 37^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula VIII or salts thereof

wherein R⁷ and R⁸ are independently selected from the group consistingof hydrogen, acyl, alkyl, alkenyl, aryl, aralkyl, Si(alkyl)₃, protectedcarboxy, alksulfonyl, and arylsulfonylcomprising:reacting a compound of Formula IV with Benzylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with acetic acid anhydride substituted by aprotected or unprotected amino;separating and isolating said compound of Formula VIII or salts thereof

In a 38^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromalkylmagnesium alkyl or arylmagnesium aryl to form a magnesium salt,wherein said alkylmagnesium alkyl and arylmagnesium aryl may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, protected acyl, nitro, protectedamino, halo and protected carboxy;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 39^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride, adipicacid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaicacid anhydride, phthalic acid anhydride, maleic acid anhydride, andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano; separating and isolating said compound of Formula III or saltsthereof.

In a 40^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of succinic acid anhydride, glutaric acid anhydride andacetic acid anhydride, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy andcyano;separating and isolating said compound of Formula III or salts thereof.

In a 41^(st) embodiment, the invention is represented by the process tomanufacture a compound of Formula V or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with succinic acid anhydride;separating and isolating said compound of Formula V or salts thereof.

In a 42nd embodiment, the invention is represented by the process tomanufacture a compound of Formula VI or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with glutaric acid anhydride;separating and isolating said compound of Formula VI or salts thereof.

In a 43^(rd) embodiment, the invention is represented by the process tomanufacture a compound of Formula VII or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with acetic acid anhydride;separating and isolating said compound of Formula VII or salts thereof.

In a 44^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula VIII or salts thereof

wherein R⁷ and R⁸ are independently selected from the group consistingof hydrogen, acyl, alkyl, alkenyl, aryl, aralkyl, Si(alkyl)₃, protectedcarboxy, alksulfonyl, and arylsulfonylcomprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesiumand Diphenylmagnesium to form a magnesium salt;reacting said magnesium salt with acetic acid anhydride substituted by aprotected or unprotected amino;separating and isolating said compound of Formula VIII or salts thereof

In a 45^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula I or salts thereof

wherein R¹, R², R³, and R⁴ are independently selected from the groupconsisting of hydrogen and alkyl, said alkyl optionally substituted byhydroxy, alkyl, alkenyl, acyl, nitro, amino, halo, carboxy and cyano;R⁵ and R⁶ are the same or different and independently selected from thegroup consisting of alkyl, alkenyl, and aryl all of which can beoptionally substituted by hydroxy, alkyl, alkenyl, acyl, nitro, amino,halo, carboxy and cyano;R⁵ and R⁶ can come together to form a carbocyclic ring; X is selectedfrom the group consisting of hydrogen, an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula II

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined, with aGrignard Reagent to form a magnesium salt or a reagent selected from thegroup consisting of an alkyl lithium, alkenyl lithium, alkynyl lithium,aryl lithium, aralkyl lithium, and a heteroaryl lithium, all which canbe optionally substituted to form a lithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated alkyl halide,saturated or unsaturated alkyl-O-sulfonyl alkyl, a saturated orunsaturated alkyl-O-sulfonyl aryl, a saturated or unsaturatedalkyl-O-acyl, and a saturated or unsaturated epoxide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, halo, protected carboxy, epoxide and cyano; separating andisolating said compound of Formula I or salts thereof.

In a 46^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof

wherein:X is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated alkyl having from 1 to 10 carbon atoms, and anoptionally substituted saturated alkyl having from 1 to 10 carbon atoms,said optionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV

with a Grignard Reagent to form a magnesium salt or a reagent selectedfrom the group consisting of an alkyl lithium, alkenyl lithium, alkynyllithium, aryl lithium, aralkyl lithium, and a heteroaryl lithium, allwhich can be optionally substituted to form a lithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated alkyl halide,saturated or unsaturated alkyl-O-sulfonyl alkyl, a saturated orunsaturated alkyl-O-sulfonyl aryl, a saturated or unsaturatedalkyl-O-acyl, and a saturated or unsaturated epoxide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, halo, protected carboxy, epoxide and cyano; separating andisolating said compound of Formula III or salts thereof.

In a 47^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent to form amagnesium salt or a reagent selected from the group consisting of analkyl lithium, alkenyl lithium, alkynyl lithium, aryl lithium, aralkyllithium, and a heteroaryl lithium, all which can be optionallysubstituted to form a lithium salt;reacting said magnesium salt or lithium salt with a compound selectedfrom the group consisting of a saturated or unsaturated alkyl halide,saturated or unsaturated alkyl-O-sulfonyl alkyl, a saturated orunsaturated alkyl-O-sulfonyl aryl, a saturated or unsaturatedalkyl-O-acyl, and a saturated or unsaturated epoxide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, halo, protected carboxy, epoxide and cyano; separating andisolating said compound of Formula III or salts thereof.

In a 48^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is selected from the group consisting of hydrogen, an optionallysubstituted unsaturated alkyl having from 1 to 10 carbon atoms, and anoptionally substituted saturated alkyl having from 1 to 10 carbon atoms,said optionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent to form amagnesium salt; reacting said magnesium salt with a compound selectedfrom the group consisting of a saturated or unsaturated alkyl halide,saturated or unsaturated alkyl-O-sulfonyl alkyl, a saturated orunsaturated alkyl-O-sulfonyl aryl, a saturated or unsaturatedalkyl-O-acyl, and a saturated or unsaturated epoxide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, halo, protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 49th embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent to form amagnesium salt; reacting said magnesium salt with a compound selectedfrom the group consisting of a saturated or unsaturated alkyl halide,saturated or unsaturated alkyl-O-sulfonyl alkyl, a saturated orunsaturated alkyl-O-sulfonyl aryl, a saturated or unsaturatedalkyl-O-acyl, and a saturated or unsaturated epoxide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, halo, protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 50^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of alkylmagnesium halide, alkenylmagnesium halide,alkynylmagnesium halide, arylmagnesium halide, arylalkylmagnesiumhalide, alkylmagnesium alkyl, arylmagnesium aryl, arylalkynylmagnesiumhalide, arylalkenylmagnesium halide, and heteroarylmagnesium halide, allof which may optionally be substituted by one or more selected from thegroup consisting of protected hydroxy, alkyl, alkenyl, protected acyl,nitro, protected amino, halo and protected carboxy, to form a magnesiumsalt;reacting said magnesium salt with a compound selected from the groupconsisting of a saturated or unsaturated alkyl halide, saturated orunsaturated alkyl-O-sulfonyl alkyl, a saturated or unsaturatedalkyl-O-sulfonyl aryl, a saturated or unsaturated alkyl-O-acyl, and asaturated or unsaturated epoxide, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 51^(st) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of alkylmagnesium halide,alkenylmagnesium halide, alkynylmagnesium halide, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, protected acyl, nitro,protected amino, halo and protected carboxy, to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 52^(nd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of Methylmagnesium bromide;Octadecylmagnesium chloride; Tetradecylmagnesium chloride;n-Pentadecylmagnesium bromide; Ethynylmagnesium chloride;n-Nonylmagnesium bromide; n-Octylmagnesium chloride;(2-Methylpropenyl)magnesium bromide; Cyclopentylmagnesium bromide;tert-Pentyl magnesium chloride; Cyclopropylmagnesium bromide;(1-Methyl-2-propenyl)magnesium chloride; 1-Decylmagnesium bromide;1-Octylmagnesium bromide; 1-Propynylmagnesium bromide; Dodecylmagnesiumbromide; sec-Butylmagnesium chloride; 1-Propenylmagnesium bromide;Isopropenylmagnesium bromide; (2,2-Dimethylpropyl)magnesium chloride;1-Heptylmagnesium bromide; 3-Butenylmagnesium bromide; 1-Pentylmagnesiumchloride; 2-Methylpropylmagnesium chloride;(2-Methyl-2-propenyl)magnesium chloride; Ethynylmagnesium bromide;1-Hexylmagnesium bromide; Vinylmagnesium chloride; Allylmagnesiumchloride; Ethylmagnesium chloride; n-Propylmagnesium chloride;Vinylmagnesium bromide; Allylmagnesium bromide; Isopropylmagnesiumchloride; Isopropylmagnesium bromide; Cyclohexylmagnesium chloride;Cyclohexylmagnesium bromide; 1-Propylmagnesium bromide;Isobutylmagnesium bromide; Ethylmagnesium bromide; 2-Butylmagnesiumbromide; 2-Propylmagnesium bromide; Methylmagnesium iodide;n-Butylmagnesium chloride; n-Butylmagnesium bromide; tert-Butylmagnesiumchloride; and Methylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 53^(rd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of Methylmagnesium bromide;Octadecylmagnesium chloride; Tetradecylmagnesium chloride;n-Nonylmagnesium bromide; n-Octylmagnesium chloride;(2-Methylpropenyl)magnesium bromide; Cyclopentylmagnesium bromide;tert-Pentyl magnesium chloride; Cyclopropylmagnesium bromide;1-Decylmagnesium bromide; 1-Octylmagnesium bromide; Dodecylmagnesiumbromide; sec-Butylmagnesium chloride; (2,2-Dimethylpropyl)magnesiumchloride; 1-Heptylmagnesium bromide; 1-Pentylmagnesium chloride;2-Methylpropylmagnesium chloride; 1-Hexylmagnesium bromide;Ethylmagnesium chloride; n-Propylmagnesium chloride; Isopropylmagnesiumchloride; Isopropylmagnesium bromide; Cyclohexylmagnesium chloride;Cyclohexylmagnesium bromide; 1-Propylmagnesium bromide;Isobutylmagnesium bromide; Ethylmagnesium bromide; 2-Butylmagnesiumbromide; 2-Propylmagnesium bromide; Methylmagnesium iodide;n-Butylmagnesium chloride; n-Butylmagnesium bromide; tert-Butylmagnesiumchloride; and Methylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which mayoptionally be substituted by one or more selected from the groupconsisting of protected hydroxy, alkyl, alkenyl, acyl, nitro, protectedamino, halo, protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 54^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of Methylmagnesium bromide;n-Octylmagnesium chloride; (2-Methylpropenyl)magnesium bromide;Cyclopentylmagnesium bromide; tert-Pentyl magnesium chloride;Cyclopropylmagnesium bromide; 1-Octylmagnesium bromide;sec-Butylmagnesium chloride; (2,2-Dimethylpropyl)magnesium chloride;1-Heptylmagnesium bromide; 1-Pentylmagnesium chloride;2-Methylpropylmagnesium chloride; 1-Hexylmagnesium bromide;Ethylmagnesium chloride; n-Propylmagnesium chloride; Isopropylmagnesiumchloride; Isopropylmagnesium bromide; Cyclohexylmagnesium chloride;Cyclohexylmagnesium bromide; 1-Propylmagnesium bromide;Isobutylmagnesium bromide; Ethylmagnesium bromide; 2-Butylmagnesiumbromide; 2-Propylmagnesium bromide; Methylmagnesium iodide;n-Butylmagnesium chloride; n-Butylmagnesium bromide; tert-Butylmagnesiumchloride; and Methylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 55^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of n-Octylmagnesium chloride;(2-Methylpropenyl)magnesium bromide; Ethylmagnesium chloride;n-Propylmagnesium chloride; Isopropylmagnesium chloride;Isopropylmagnesium bromide; Cyclohexylmagnesium chloride;Methylmagnesium iodide; n-Butylmagnesium chloride; tert-Butylmagnesiumchloride; and Methylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 56^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with isopropylmagnesiumchloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 57^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula IX, X, XI or XII or salts thereof

comprising:reacting a solution of a compound of Formula IV with isopropylmagnesiumchloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutyrate, aralkyl4-halobutyrate, and butyrolactone; separating and isolating saidcompound of Formula IX, X, XI or XII or salts thereof.

In a 58^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula XIII, XIV, XV or XVI or salts thereof

comprising:reacting a compound of Formula IV with isopropylmagnesium chloride toform a magnesium salt;reacting said magnesium salt with alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and alkali metal haloacetate;separating and isolating said compound of Formula XIII, XIV, XV or XVIor salts thereof.

In a 59^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula XVII or salts thereof

comprising:reacting a compound of Formula IV with isopropylmagnesium chloride toform a magnesium salt;reacting said magnesium salt with diepoxybutane;separating and isolating said compound of Formula XVI or salts thereof.

In a 60^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from arylmagnesium halide or heteroarylmagnesium halide to forma magnesium salt, wherein said arylmagnesium halide andheteroarylmagnesium halide may optionally be substituted by one or moreselected from the group consisting of protected hydroxy, alkyl, alkenyl,protected acyl, nitro, protected amino, halo and protected carboxy;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 61^(st) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Chloro-4-fluorophenylmagnesium bromide;3-Fluoro-2-methylphenylmagnesium bromide;5-Fluoro-2-methoxyphenylmagnesium bromide;5-Fluoro-2-methylphenylmagnesium bromide;3,5-Dimethyl-4-methoxyphenylmagnesium bromide;3-Fluoro-4-methylphenylmagnesium bromide;3-[Bis(trimethylsilyl)amino]phenylmagnesium chloride; 3-Thienylmagnesiumiodide; 3-Fluoro-4-chlorophenylmagnesium bromide;3,4,5-Trifluorophenylmagnesium bromide;4-Methoxy-2-methylphenylmagnesium bromide; 2,4-Dimethoxyphenylmagnesiumbromide; 2,3-Dimethylphenylmagnesium bromide; 3-Methylphenylmagnesiumchloride; (4-methyl-1-naphthalenyl)magnesium bromide;(3-fluoro-4-methoxyphenyl)magnesium bromide; 2-Chloro-5-thienylmagnesiumbromide; 3,4-Dimethylphenylmagnesium chloride;3-Methyl-2-thienylmagnesium bromide; Pentamethylphenylmagnesium bromide;3,4-Dimethoxyphenylmagnesium bromide; (3,4-Dimethylphenyl)magnesiumbromide; (3,5-Dichlorophenyl)magnesium bromide;(4-Fluoro-3-methylphenyl)magnesium bromide; 3,4-Dichlorophenylmagnesiumbromide; 2,3,5,6-Tetramethylphenylmagnesium bromide; 9-Phenanthrylmagnesium bromide; (4-tert-Butylphenyl)magnesium bromide;2,5-Dimethoxyphenylmagnesium bromide; 3,5-Difluorophenylmagnesiumbromide; 4-Chlorophenylmagnesium chloride;(6-Methoxy-2-naphthyl)magnesium bromide; (2-Methoxy-1-naphthyl)magnesiumbromide; 3-Methoxyphenylmagnesium bromide; (3-Chlorophenyl)magnesiumbromide; (3,5-Dimethylphenyl)magnesium bromide;(2-Methylphenyl)magnesium chloride; 4-Fluoro-2-methylphenylmagnesiumbromide; (2,5-Dimethylphenyl)magnesium bromide; m-Methylphenylmagnesiumbromide; 4-Ethylphenylmagnesium bromide; 2-Pyridylmagnesium bromide;4-Phenoxyphenylmagnesium bromide; 2-Naphthylmagnesium bromide;(2-Methyl-1-naphthyl)magnesium bromide; 2,6-Dimethylphenylmagnesiumbromide; 2-Ethylphenylmagnesium bromide; 4-(Methylthio)phenylmagnesiumbromide; (4-Isopropylphenyl)magnesium bromide;3,4-Methylenedioxyphenylmagnesium bromide; 3-Fluorophenylmagnesiumbromide; (o-Methoxyphenyl)magnesium bromide; Phenylmagnesium iodide;(4-Methoxyphenyl)magnesium bromide; 4-(Dimethylamino)phenylmagnesiumbromide; 2-Thienylmagnesium bromide; (4-Methylphenyl)magnesium bromide;Mesitymagnesium bromide; 2-Tolylmagnesium bromide;Pentafluorophenylmagnesium bromide; (4-Chlorophenyl)magnesium bromide;1-Naphthalenylmagnesium bromide; 4-Methylphenylmagnesium chloride;4-Fluorophenylmagnesium bromide; Phenylmagnesium chloride;Phenylmagnesium bromide; and (4-Biphenylyl)magnesium bromide to form amagnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 62^(nd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3,5-Dimethyl-4-methoxyphenylmagnesium bromide;4-Methoxy-2-methylphenylmagnesium bromide; 2,4-Dimethoxyphenylmagnesiumbromide; 2,3-Dimethylphenylmagnesium bromide; 3-Methylphenylmagnesiumchloride; 3,4-Dimethylphenylmagnesium chloride;Pentamethylphenylmagnesium bromide; 3,4-Dimethoxyphenylmagnesiumbromide; (3,4-Dimethylphenyl)magnesium bromide;2,3,5,6-Tetramethylphenylmagnesium bromide;(4-tert-Butylphenyl)magnesium bromide; 2,5-Dimethoxyphenylmagnesiumbromide; 3-Methoxyphenylmagnesium bromide; (3,5-Dimethylphenyl)magnesiumbromide; (2-Methylphenyl)magnesium chloride;(2,5-Dimethylphenyl)magnesium bromide; m-Methylphenylmagnesium bromide;4-Ethylphenylmagnesium bromide; 4-Phenoxyphenylmagnesium bromide;2,6-Dimethylphenylmagnesium bromide; 2-Ethylphenylmagnesium bromide;(4-Isopropylphenyl)magnesium bromide; 3,4-Methylenedioxyphenylmagnesiumbromide; (o-Methoxyphenyl)magnesium bromide; Phenylmagnesium iodide;(4-Methoxyphenyl)magnesium bromide; (4-Methylphenyl)magnesium bromide;Mesitymagnesium bromide; 2-Tolylmagnesium bromide;4-Methylphenylmagnesium chloride; Phenylmagnesium chloride; andPhenylmagnesium bromide to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 63^(rd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methylphenylmagnesium chloride;(4-tert-Butylphenyl)magnesium bromide; 3-Methoxyphenylmagnesium bromide;(2-Methylphenyl)magnesium chloride; m-Methylphenylmagnesium bromide;4-Ethylphenylmagnesium bromide; 2-Ethylphenylmagnesium bromide;(4-Isopropylphenyl)magnesium bromide; (o-Methoxyphenyl)magnesiumbromide; Phenylmagnesium iodide; (4-Methoxyphenyl)magnesium bromide;(4-Methylphenyl)magnesium bromide; 2-Tolylmagnesium bromide;4-Methylphenylmagnesium chloride; Phenylmagnesium chloride; andPhenylmagnesium bromide to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 64^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methylphenylmagnesium chloride;3-Methoxyphenylmagnesium bromide; (2-Methylphenyl)magnesium chloride;m-Methylphenylmagnesium bromide; (o-Methoxyphenyl)magnesium bromide;Phenylmagnesium iodide; (4-Methoxyphenyl)magnesium bromide;(4-Methylphenyl)magnesium bromide; 2-Tolylmagnesium bromide;4-Methylphenylmagnesium chloride; Phenylmagnesium chloride; andPhenylmagnesium bromide to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 65^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 66^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutrate, aralkyl4-halobutyrate, butyrolactone, alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and diepoxybutane, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 67^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula IX, X, XI or XII or salts thereof

comprising:reacting a solution of a compound of Formula IV with a Grignard Reagentselected from the group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with a compound from the group consistingof alkyl 4-halobutyrate, aryl 4-halobutyrate, aralkyl 4-halobutyrate,and butyrolactone;separating and isolating said compound of Formula IX, X, XI or XII orsalts thereof.

In a 68^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula XIII, XIV, XV or XVI or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and alkali metal haloacetate;separating and isolating said compound of Formula XIII, XIV, XV or XVIor salts thereof.

In a 69^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula XVII or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 3-Methoxyphenylmagnesium bromide;(o-Methoxyphenyl)magnesium bromide; and Phenylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with diepoxybutane;separating and isolating said compound of Formula XVII or salts thereof.

In a 70^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of arylalkylmagnesium halide, arylalkynylmagnesiumhalide, and arylalkenylmagnesium halide to form a magnesium salt, all ofwhich may optionally be substituted by one or more selected from thegroup consisting of protected hydroxy, alkyl, alkenyl, protected acyl,nitro, protected amino, halo and protected carboxy; reacting saidmagnesium salt with a compound selected from the group consisting of asaturated or unsaturated alkyl halide, saturated or unsaturatedalkyl-O-sulfonyl alkyl, a saturated or unsaturated alkyl-O-sulfonylaryl, a saturated or unsaturated alkyl-O-acyl, and a saturated orunsaturated epoxide, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy, epoxideand cyano;separating and isolating said compound of Formula III or salts thereof.

In a 71^(st) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 2,5-Dimethylbenzylmagnesium chloride;2,6-Dichlorobenzylmagnesium chloride; 2,4-Dichlorobenzylmagnesiumchloride; 2-Fluorobenzylmagnesium chloride; 2,4-Dimethylbenzylmagnesiumchloride; 3-Bromobenzylmagnesium bromide; 4-Bromobenzylmagnesiumbromide; (2-Phenylethyl)magnesium chloride; 3-Fluorobenzylmagnesiumchloride; (3,4-Dichlorobenzyl)magnesium chloride; 2-Bromobenzylmagnesiumbromide; 4-Methoxybenzylmagnesium chloride; 4-Methylbenzylmagnesiumchloride; m-Methylbenzylmagnesium chloride; 2-Methylbenzylmagnesiumchloride; 3-Chlorobenzylmagnesium chloride; 2-Chlorobenzylmagnesiumchloride; m-Methoxybenzylmagnesium chloride; Benzylmagnesium chloride;(Phenylethynyl)magnesium bromide; 4-Fluorobenzylmagnesium chloride;Benzylmagnesium bromide; 4-Chlorobenzylmagnesium chloride; and2-Chloro-6-fluorobenzylmagnesium chloride to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of a saturated or unsaturated alkyl halide, saturated orunsaturated alkyl-O-sulfonyl alkyl, a saturated or unsaturatedalkyl-O-sulfonyl aryl, a saturated or unsaturated alkyl-O-acyl, and asaturated or unsaturated epoxide, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 72^(nd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of 2,5-Dimethylbenzylmagnesium chloride;2,4-Dimethylbenzylmagnesium chloride; (2-Phenylethyl)magnesium chloride;4-Methoxybenzylmagnesium chloride; 4-Methylbenzylmagnesium chloride;m-Methylbenzylmagnesium chloride; 2-Methylbenzylmagnesium chloride;m-Methoxybenzylmagnesium chloride; Benzylmagnesium chloride; andBenzylmagnesium bromide to form a magnesium salt; reacting saidmagnesium salt with a compound selected from the group consisting of asaturated or unsaturated alkyl halide, saturated or unsaturatedalkyl-O-sulfonyl alkyl, a saturated or unsaturated alkyl-O-sulfonylaryl, a saturated or unsaturated alkyl-O-acyl, and a saturated orunsaturated epoxide, all of which may optionally be substituted by oneor more selected from the group consisting of protected hydroxy, alkyl,alkenyl, acyl, nitro, protected amino, halo, protected carboxy, epoxideand cyano;separating and isolating said compound of Formula III or salts thereof.

In a 73^(rd) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with Benzylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of a saturated or unsaturated alkyl halide, saturated orunsaturated alkyl-O-sulfonyl alkyl, a saturated or unsaturatedalkyl-O-sulfonyl aryl, a saturated or unsaturated alkyl-O-acyl, and asaturated or unsaturated epoxide, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 74^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula IX, X, XI or XII or salts thereof

comprising:reacting a solution of a compound of Formula IV with Benzylmagnesiumchloride to form a magnesium salt;reacting said magnesium salt with a compound selected form the groupconsisting of alkyl 4-halobutyrate, aryl 4-halobutyrate, aralkyl4-halobutyrate and butyrolactone; separating and isolating said compoundof Formula IX, X, XI or XII or salts thereof.

In a 75^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula XIII, XIV, XV or XVI or salts thereof

comprising:reacting a compound of Formula IV with Benzylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and alkali metal haloacetate;separating and isolating said compound of Formula XIII, XIV, XV or XVIor salts thereof.

In a 76th embodiment, the invention is represented by the process tomanufacture a compound of Formula XVII or salts thereof

comprising:reacting a compound of Formula IV with Benzylmagnesium chloride to forma magnesium salt;reacting said magnesium salt with diepoxybutane;separating and isolating said compound of Formula XVII or salts thereof.

In a 77^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromalkylmagnesium alkyl or arylmagnesium aryl to form a magnesium salt,wherein said alkylmagnesium alkyl and arylmagnesium aryl may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, protected acyl, nitro, protectedamino, halo and protected carboxy;reacting said magnesium salt with a compound selected from the groupconsisting of a saturated or unsaturated alkyl halide, saturated orunsaturated alkyl-O-sulfonyl alkyl, a saturated or unsaturatedalkyl-O-sulfonyl aryl, a saturated or unsaturated alkyl-O-acyl, and asaturated or unsaturated epoxide, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In a 78^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula III or salts thereof wherein:

X is hydrogen;

Y is selected from the group consisting of an optionally substitutedunsaturated alkyl having from 1 to 10 carbon atoms, and an optionallysubstituted saturated alkyl having from 1 to 10 carbon atoms, saidoptionally substituted unsaturated alkyl and optionally substitutedsaturated alkyl optionally containing a polar or charged functionality;comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of a saturated or unsaturated alkyl halide, saturated orunsaturated alkyl-O-sulfonyl alkyl, a saturated or unsaturatedalkyl-O-sulfonyl aryl, a saturated or unsaturated alkyl-O-acyl, and asaturated or unsaturated epoxide, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, halo,protected carboxy, epoxide and cyano;separating and isolating said compound of Formula III or salts thereof.

In an 79^(th) embodiment, the invention is represented by the process tomanufacture a compound of Formula IX, X, XI or XII or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with a compound from the group consistingof alkyl 4-halobutyrate, aryl 4-halobutyrate, aralkyl 4-halobutyrate,and butyrolactone; separating and isolating said compound of Formula IX,X, XI or XII or salts thereof.

In an 80^(st) embodiment, the invention is represented by the process tomanufacture a compound of Formula XIII, XIV, XV or XVI or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with alkyl haloacetate, aryl haloacetate,aralkyl haloacetate, and alkali metal haloacetate;separating and isolating said compound of Formula XIII, XIV, XV or XVIor salts thereof.

In an 81^(nd) embodiment, the invention is represented by the process tomanufacture a compound of Formula XVII or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent selected fromthe group consisting of n-Butyl-sec-butylmagnesium; Dimethylmagnesium;Di-n-Butylmagnesium; Diethylmagnesium; and Diphenylmagnesium to form amagnesium salt;reacting said magnesium salt with diepoxybutane;separating and isolating said compound of Formula XVII or salts thereof.

In an 82^(nd) embodiment, the invention is represented by the process tomanufacture a compound of Formula XII or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent to form amagnesium salt;reacting said magnesium salt with alkyl haloacetate, aryl haloacetate oraralkyl haloacetate to form the compound of IX, X or XI;hydrolyzing said compound of IX, X or XI;separating and isolating said compound of Formula XII or salts thereof.

In an 83^(rd) embodiment, the invention is represented by the process tomanufacture a compound of Formula XVI or salts thereof

comprising:reacting a compound of Formula IV with a Grignard Reagent to form amagnesium salt;reacting said magnesium salt with alkyl haloacetate, aryl haloacetate,or aralkyl haloacetate to form the compound of XIII, XIV or XV;hydrolyzing said compound of XIII, XIV or XV;separating and isolating said compound of Formula XVI or salts thereof.

DEFINITIONS

The terms “alkyl” or “alk”, alone or in combination, unless otherwisespecified, refers to a saturated straight, branched or cyclic primary,secondary, or tertiary hydrocarbon from 1 to 18 carbon atoms andspecifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl,butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl,hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl, trifluoromethyl andperfluoroalkyl. The term includes both substituted and unsubstitutedalkyl groups. The alkyl group can be substituted with any moiety thatdoes not adversely affect the properties of the active compound, forexample, but not limited to hydroxyl, halo (including independently F,Cl, Br, and I), perfluoro alkyl including trifluoromethyl, amino,alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, acyl, amido,carboxamido, carboxylate, thiol, alkylthio, azido, sulfonic acid,sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected,or protected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991, herebyincorporated by reference. In one embodiment, the alkyl can be, forexample, CF₃, CH₂CF₃, CCl₃, or cyclopropyl.

In the text, whenever the term C (alkyl range) is used, the termindependently includes each member of that class as if specifically andseparately set out. As a non-limiting example, the term “C₁₋₁₀”independently represents each species that falls within the scope,including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, neo-pentyl,cyclopentyl, cyclopentyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 4-ethyl butyl, cyclohexyl, heptyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,6-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl,4-ethylpentyl, 5-ethylpentyl, 1-propylbutyl, 2-propylbutyl,3-propylbutyl, 4-propylbutyl, cycloheptyl, octyl, 1-methylheptyl,2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,6-methylheptyl, 7-methylheptyl, 1-ethylhexyl, 2-ethylhexyl,3-ethylhexyl, 4-ethylhexyl, 5-ethylhexyl, 6-ethylhexyl, 1-propylpentyl,2-propylpentyl, 3-propylpentyl, 4-propylpentyl, 5-propylpentyl,cyclooctyl, nonyl, cyclononyl, decyl, or cyclodecyl. C₁₋₆, C₁₋₈, C₂₋₈,C₃₋₈, C₁₋₁₀ and C₁₋₁₈ likewise can independently include any of itsmember groups, as if each were independently named herein.

The term “alkenyl”, alone or in combination, unless otherwise specifiedrefers to a straight, branched or cyclic hydrocarbon having from 2 to 10carbon atoms and containing one or more double carbon-carbon bonds.Examples of such radicals are methylene, ethylene, methylethylene, andisopropylidene. Included within the scope of this term are1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl,1,3-butane-diyl, 1,4-butane-diyl and the like. The alkylene group orother divalent moiety disclosed herein can be optionally substitutedwith one or more moieties selected from the group consisting of alkyl,halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido,carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy,aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl,sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl,phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide,anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, orany other viable functional group that does not inhibit thepharmacological activity of this compound, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991, herebyincorporated by reference.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbonradical, linear or branched, in so much as it contains one or moretriple bonds, including such radicals containing about 2 to 10 carbonatoms or having from 2 to 6 carbon atoms. Said alkynyl radicals may beoptionally substituted with groups as defined below. Examples ofsuitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl,butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl,3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl,3,3-dimethylbutyn-1-yl radicals and the like.

The term “aryl” or “ar”, alone or in combination, means a carbocyclicaromatic system containing one, two or three rings wherein such ringsmay be attached together in a pendent manner or may be fused. The term“aryl” also includes an “aryl” optionally substituted with one or moreof the moieties selected from the group consisting of alkyl, alkenyl,and alkynyl, alkoxy, aryloxy, halo, and amino.

The term “acyl”, alone or in combination, refers to a group of theformula C(O)R′, wherein R′ is hydrogen, alkyl, alkenyl, alkynyl, aryl,or aralkyl group. Examples of “acyl” are formyl, acetyl, benzoyl,trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.

The term “amino”, alone or in combination, refers to the radical —NH₂ or—NH—, or

The term “alkoxy”, alone or in combination, refers to an alkyl group asdefined herein bonded through an oxygen linkage. Examples of alkoxysinclude methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxyalkyls.

The term “aryloxy”, alone or in combination, refers to an aryl group asdefined herein bonded through an oxygen linkage.

The term “alkthio”, alone or in combination, refers to an alkyl group asdefined herein bonded through a sulfur linkage.

The term “carboxy”, refers to the radical

The terms “halo” and “halogen” and “halide”, alone or in combination,refer to chloro, bromo, iodo and fluoro.

The term “substituted”, means that one or more hydrogen on thedesignated atom or substituent is replaced provided that the designatedatom's normal valency is not exceeded, and the that the substitutionresults in a stable compound. Typical substitutions include, hydroxy,alkyl, alkenyl, acyl, nitro, amino, halo, carboxy, cyano and protectinggroups as defined herein. Such substitutions can be further substituted.

The term “polar or charged functionality” refers to a polar or chargedgroup attached in place of one or more hydrogen atoms. Non limitingexamples include carboxy, hydroxy, amino, epoxide, etc.

The terms “heteroaryl”, alone or in combination, refer to an aryl asdefined herein containing at least one heteroatom selected from sulfur,oxygen, nitrogen or phosphorus. The heteroaryl may optionally besubstituted as that term is used herein and/or substituted with aprotecting group as that term is used herein. In addition, adjacentgroups on the heteroaryl may combine to form a 5- to 7-memberedcarbocyclic, aryl, heteroaryl, which in turn may be substituted asabove. Nonlimiting examples of heteroaryls are pyrrolidinyl,tetrahydrofuryl, tetrahydrofuranyl, pyranyl, purinyl, tetrahydropyranyl,piperazinyl, piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl,imidazolyl, pyrolinyl, pyrazolinyl, indolinyl, dioxolanyl, or1,4-dioxanyl, aziridinyl, furyl, furanyl, pyridyl, pyridinyl,pyridazinyl, pyrimidinyl, benzoxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazole, indazolyl, triazinayl,1,3,5-triazinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl,pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl,isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl,carbazolyl, oxazolyl, thiazolyl, benzothiazolyl, isothiazolyl,1,2,4-thiadiazolyl, isooxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,pyrrolyl, quinazolinyl, quinoxalinyl, benzoxazolyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl,pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole,thiazine, pyridazine, triazolopyridinyl or pteridinyl, wherein saidheteroaryl can be optionally substituted.

The terms “protecting group” or “protected” refers to a substituent thatprotects various sensitive or reactive groups present, so as to preventsaid groups from interfering with a reaction. Such protection may becarried out in a well-known manner as taught by Greene, et al.,Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991 or of the like. The protecting group may be removed afterthe reaction in any manner known by those skilled in the art.Non-limiting examples of protecting groups include trimethylsilyl,dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl,trityl or substituted trityl, alkyl groups, acyl groups such as acetyland propionyl, methanesulfonyl, and p-toluenesulfonyl. For example, aprotected carboxy could be selected from one of the following:

The term “carboxylic acid anhydride”, alone or in combination refers tocompounds having the formulas acyl-OC(O)R^(α), acyl-OC(O)OR^(α),acyl-OC(O)SR^(α), or acyl-OC(O)NR^(α)R^(β) wherein R^(α) is selectedfrom the group consisting of alkyl, alkenyl, alkynyl, aryl, and aralkyland R^(β) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, alkaryl, aralkyl and a protecting group (as that term isdefined herein). The term “carboxylic anhydride” includes “cycliccarboxylic acid anhydride”, which refers to compounds having the formula

wherein Z is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl and—(CH₂)NR^(β). All “carboxylic acid anhydrides” may optionally besubstituted as defined herein.

The term “activated carboxylic acid ester” refers to compounds havingthe formula C(O)SR″ and C(O)OR″, wherein R″ is a substituted orunsubstituted aryl or an unsubstituted or substituted alkyl.

The term “Grignard Reagent” generally means an organic magnesium halide(as defined by The Columbia Encyclopedia, Sixth Edition, 2001, hereinincorporated by reference) or a bis-organic magnesium compoundrepresented by the formulas R^(γ)MgX and R^(γ)MgR^(δ) respectively,wherein R^(γ) and R^(δ) are independently selected from the groupconsisting of a primary, secondary, or tertiary alkyl; alkenyl; alkynyl;aralkyl; heteroaryl; and aryl, all of which can be substituted as thatterm is defined herein, and X is represented by a halide.

The term “sulfonyl” refers to the radical

The term “alksulfonyl” refers to the radical

The term “epoxide” refers to

wherein all R groups are independently selected from hydrogen, alkyl,aryl and arylalkyl wherein said alkyl, aryl and arylalkyl may optionallybe substituted with a polar functionality.

The terms “esters of probucol” and “esters of probucol derivatives” aredefined as probucol or probucol derivatives (as the case may be) whereinone or both of the phenol moieties are acylated. The terms “monoestersof probucol” and “monoesters of probucol derivatives” are defined asprobucol or probucol derivatives (as the case may be) wherein one of thephenol moieties are acylated.

The terms “ethers of probucol” and “ethers of probucol derivatives” aredefined as probucol or probucol derivatives (as the case may be) whereinone or both of the phenol moieties are alkylated. The terms “monoethersof probucol” and “monoethers of probucol derivatives” are defined asprobucol or probucol derivatives (as the case may be) wherein one of thephenol moieties are alkylated.

The term “probucol derivative” refers to the compound

wherein at least one R¹, R², R³, and R⁴ is other than t-butyl and/or oneor both of R⁵ and R⁶ are other than methyl and/or one or both of X and Yare other than hydrogen.

EXAMPLES

The following examples are provided to illustrate the present inventionand are not intended to limit the scope thereof. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used tomanufacture the desired compounds. The materials required for theembodiments and the examples are known in the literature, readilycommercially available, or can be made by known methods from knownstarting materials by those skilled in the art.

Example 1

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF)in 1 portion. The reaction was brought to room temperature and thensuccinic anhydride (0.25 g, 2.5 mmol) was added in 1 portion. Afteraging for 45 min, the reaction was slowly quenched with 1 N HCl anddiluted with EtOAc. The biphasic reaction was then cooled to roomtemperature and the phases were separated. Analysis by HPLC of theorganic layer indicated 60% probucol monosuccinate, 13% probucoldisuccinate, and 27% probucol.

Example 2

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium bromide (1.0 mL, 1.0 M in THF) in1 portion. The reaction was brought to room temperature and thensuccinic anhydride (0.25 g, 2.5 mmol) was added in 1 portion followed byanhydrous THF (0.5 mL). After aging for 1.5 h, the reaction was slowlyquenched with 1 N HCl and diluted with EtOAc. The biphasic reaction wasthen cooled to room temperature and the phases were separated. Analysisby HPLC of the organic layer indicated 55% probucol monosuccinate, 27%probucol disuccinate, and 18% probucol.

Example 3

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) and succinic anhydride (0.25 g, 2.5 mmol) followed by 2.5 mLanhydrous toluene. To the resulting solution was addedisopropylmagnesium chloride (0.51 mL, 2.0 M in THF) over 2 min. Afteraging for 40 min, the reaction was slowly quenched with 1 N HCl anddiluted with EtOAc. The biphasic reaction was then cooled to roomtemperature and the phases were separated. Analysis by HPLC of theorganic layer indicated 53% probucol monosuccinate, 17% probucoldisuccinate, and 30% probucol.

Example 4

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF)in 1 portion. The reaction temperature was brought to 5° C. and thensuccinic anhydride (0.25 g, 2.5 mmol) was added in 1 portion. Afteraging for 45 min, the reaction was slowly quenched with 1 N HCl anddiluted with EtOAc. The biphasic reaction was then cooled to roomtemperature and the phases were separated. Analysis by HPLC of theorganic layer indicated 46% probucol monosuccinate, 47% probucoldisuccinate, and 7% probucol.

Example 5

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF)in 1 portion. The reaction was brought to room temperature and thensuccinic anhydride (125.0 mg, 1.25 mmol) was added as a solution in THF(1.5 mL) over 5 min. After aging for 40 min, analysis by HPLC of thereaction mixture indicated 55% probucol monosuccinate, 17% probucoldisuccinate, and 28% probucol.

Example 6

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF)in 1 portion. The reaction temperature was brought to 40° C. and thensuccinic anhydride (125.0 mg, 1.25 mmol) was added as a solution in THF(1.5 mL) over 5 min. After aging for 20 min, the reaction was slowlyquenched with 1 N HCl and diluted with EtOAc. The biphasic reaction wasthen cooled to room temperature and the phases were separated. Analysisby HPLC of the organic layer indicated 51% probucol monosuccinate, 32%probucol disuccinate, and 17% probucol.

Example 7

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF)in 1 portion. The reaction temperature was brought to 60° C. and thensuccinic anhydride (125.0 mg, 1.25 mmol) was added as a solution in THF(1.5 mL) over 5 min. After aging for 20 min, the reaction was slowlyquenched with 1 N HCl and diluted with EtOAc. The biphasic reaction wasthen cooled to room temperature and the phases were separated. Analysisby HPLC of the organic layer indicated 45% probucol monosuccinate, 45%probucol disuccinate, and 10% probucol.

Example 8

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF)in 1 portion. The reaction was brought to room temperature and thensuccinic anhydride (75.0 mg, 0.75 mmol) was added as a solution in THF(1 mL) over 5 min. After aging for 45 min, the reaction was slowlyquenched with 1 N HCl and diluted with EtOAc. The biphasic reaction wasthen cooled to room temperature and the phases were separated. Analysisby HPLC of the organic layer indicated 59% probucol monosuccinate, 20%probucol disuccinate, and 21% probucol.

Example 9

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF)in 1 portion. The reaction temperature was brought to 40° C. and thensuccinic anhydride (75.0 mg, 0.75 mmol) was added as a solution in THF(1 mL) over 5 min. After aging for 20 min, the reaction was slowlyquenched with 1 N HCl and diluted with EtOAc. The biphasic reaction wasthen cooled to room temperature and the phases were separated. Analysisby HPLC of the organic layer indicated 59% probucol monosuccinate, 20%probucol disuccinate, and 21% probucol.

Example 10

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF)in 1 portion. The reaction temperature was brought to 60° C. and thensuccinic anhydride (75.0 mg, 0.75 mmol) was added as a solution in THF(1 mL) over 5 min. After aging for 20 min, the reaction was slowlyquenched with 1 N HCl and diluted with EtOAc. The biphasic reaction wasthen cooled to room temperature and the phases were separated. Analysisby HPLC of the organic layer indicated 59% probucol monosuccinate, 26%probucol disuccinate, and 15% probucol.

Example 11

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 5 mL anhydrous toluene. To the resulting solutionwas added isopropylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1portion. The reaction was brought to room temperature and then succinicanhydride (75.0 mg, 0.75 mmol) was added as a solution in THF (1 mL)over 5 min. After aging for 45 min, analysis by HPLC of the reactionmixture indicated 54% probucol monosuccinate, 10% probucol disuccinate,and 34% probucol.

Example 12

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene and 0.5 mL anhydroushexane. To the resulting solution was added isopropylmagnesium chloride(0.51 mL, 2.0 M in THF) in 1 portion. The reaction temperature wasbrought to room temperature and then succinic anhydride (75.0 mg, 0.75mmol) was added over 5 min. After aging for 45 min, analysis by HPLC ofthe reaction mixture indicated 57% probucol monosuccinate, 16% probucoldisuccinate, and 27% probucol.

Example 13

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 5 mL anhydrous toluene. To the resulting solutionwas added cyclopentylmagnesium chloride (0.51 mL, 2.0 M in ethyl ether)in 1 portion. The reaction was brought to room temperature and thensuccinic anhydride (75.0 mg, 0.75 mmol) was added in 1 portion and agedovernight. Analysis by HPLC of the reaction mixture indicated 47%probucol monosuccinate, 14% probucol disuccinate, and 39% probucol.

Example 14

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 5 mL anhydrous toluene. To the resulting solutionwas added cyclohexylmagnesium chloride (0.51 mL, 2.0 M in ethyl ether)in 1 portion. The reaction was brought to room temperature and thensuccinic anhydride (75.0 mg, 0.75 mmol) was added in 1 portion and agedovernight. Analysis by HPLC of the reaction mixture indicated 48%probucol monosuccinate, 14% probucol disuccinate, and 38% probucol.

Example 15

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene. To the resultingsolution was added benzylmagnesium chloride (1.02 mL, 1.0 M in ethylether) in 1 portion. The reaction temperature was brought to 40° C. andthen succinic anhydride (75.0 mg, 0.75 mmol) was added in 1 portion andaged overnight. Analysis by HPLC of the reaction mixture indicated 50%probucol monosuccinate, 14% probucol disuccinate, and 36% probucol.

Example 16

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous THF. To the resulting solutionwas added benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion.The reaction temperature was brought to 60° C. and then succinicanhydride (75.0 mg, 0.75 mmol) was added in 1 portion. After aging for30 min, the reaction was slowly quenched with 1 N HCl and diluted withEtOAc. The biphasic reaction was then cooled to room temperature and thephases were separated. Analysis by HPLC of the organic layer indicated57% probucol monosuccinate, 17% probucol disuccinate, and 28% probucol.

Example 17

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous THF. To the resulting solutionwas added benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion.The reaction temperature was brought to 40° C. and then succinicanhydride (75.0 mg, 0.75 mmol) was added in 1 portion. After aging for30 min, the reaction was slowly quenched with 1 N HCl and diluted withEtOAc. The biphasic reaction was then cooled to room temperature and thephases were separated. Analysis by HPLC of the organic layer indicated53% probucol monosuccinate, 11% probucol disuccinate, and 36% probucol.

Example 18

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene and 2.0 mL anhydroustetrahydrofuran (THF). To the resulting solution was addedbenzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion. Thereaction temperature was brought to 40° C. and then succinic anhydride(75.0 mg, 0.75 mmol) was added in 1 portion. After aging for 30 min, thereaction was slowly quenched with 1 N HCl and diluted with EtOAc. Thebiphasic reaction was then cooled to room temperature and the phaseswere separated. Analysis by HPLC of the organic layer indicated 55%probucol monosuccinate, 24% probucol disuccinate, and 21% probucol.

Example 19

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous toluene and 2.0 mL anhydrousTHF. To the resulting solution was added benzylmagnesium chloride (0.51mL, 2.0 M in THF) in 1 portion. The reaction temperature was brought toroom temperature and then succinic anhydride (75.0 mg, 0.75 mmol) wasadded in 1 portion. After aging for 30 min, the reaction was slowlyquenched with 1 N HCl and diluted with EtOAc. The biphasic reaction wasthen cooled to room temperature and the phases were separated. Analysisby HPLC of the organic layer indicated 50% probucol monosuccinate, 9%probucol disuccinate, and 41% probucol.

Example 20

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 4.5 mL anhydrous THF. To the resulting solutionwas added benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion.The reaction temperature was brought to 40° C. and then succinicanhydride (75.0 mg, 0.75 mmol) was added in 1 portion. After aging for30 min, analysis by HPLC of the reaction mixture indicated 45% probucolmonosuccinate, 7% probucol disuccinate, and 48% probucol.

Example 21

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous THF. To the resulting solutionwas added benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion.The reaction temperature was brought to 50° C. and then succinicanhydride (55.0 mg, 0.55 mmol) was added in 1 portion. After aging for30 min, analysis by HPLC of the reaction mixture indicated 52% probucolmonosuccinate, 7% probucol disuccinate, and 41% probucol.

Example 22

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 2.5 mL anhydrous THF. To the resulting solutionwas added benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion.The reaction temperature was brought to 40° C. and then succinicanhydride (55.0 mg, 0.55 mmol) was added in 1 portion. After aging for30 min, analysis by HPLC of the reaction mixture indicated 51% probucolmonosuccinate, 7% probucol disuccinate, and 42% probucol.

Example 23

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 1 mL anhydrous THF. To the resulting solution wasadded benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion. Thereaction temperature was brought to 40° C. and then succinic anhydride(55.0 mg, 0.55 mmol) was added in 1 portion. After aging for 45 min,analysis by HPLC of the reaction mixture indicated 57% probucolmonosuccinate, 9% probucol disuccinate, and 34% probucol.

Example 24

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 1 mL anhydrous anisole. To the resulting solutionwas added benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion.The reaction temperature was brought to 40° C. and then succinicanhydride (55.0 mg, 0.55 mmol) was added in 1 portion. After aging for45 min, analysis by HPLC of the reaction mixture indicated 58% probucolmonosuccinate, 10% probucol disuccinate, and 32% probucol.

Example 25

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 0.5 mL anhydrous anisole. To the resultingsolution was added 2-methoxyphenylmagnesium bromide (1.02 mL, 1.0 M inTHF) in 1 portion. The reaction temperature was brought to 40° C. andthen succinic anhydride (55.0 mg, 0.55 mmol) was added in 1 portion.After aging for 45 min, analysis by HPLC of the reaction mixtureindicated 42% probucol monosuccinate, 6% probucol disuccinate, and 52%probucol.

Example 26

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 0.5 mL anhydrous anisole. To the resultingsolution was added 3-methoxyphenylmagnesium bromide (1.02 mL, 1.0 M inTHF) in 1 portion. The reaction temperature was brought to 40° C. andthen succinic anhydride (55.0 mg, 0.55 mmol) was added in 1 portion.After aging for 45 min, analysis by HPLC of the reaction mixtureindicated 45% probucol monosuccinate, 5% probucol disuccinate, and 50%probucol.

Example 27

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 1 mL anhydrous toluene. To the resulting solutionwas added benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion.The reaction temperature was brought to 40° C. and then succinicanhydride (55.0 mg, 0.55 mmol) was added in 1 portion. After slowlyquenching the reaction with 1 N HCl and diluting with EtOAc, thebiphasic reaction was cooled to room temperature and the phases wereseparated. Analysis by HPLC of the organic layer indicated 50% probucolmonosuccinate, 8% probucol disuccinate, and 42% probucol.

Example 28

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 1 mL anhydrous THF. To the resulting solution wasadded octylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion. Thereaction temperature was brought to 40° C. and then succinic anhydride(55.0 mg, 0.55 mmol) was added in 1 portion. After aging for 45 min,analysis by HPLC of the reaction mixture indicated 53% probucolmonosuccinate, 12% probucol disuccinate, and 35% probucol.

Example 29

In a dry 25 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g,0.48 mmol) followed by 0.25 mL anhydrous THF. To the resulting solutionwas added benzylmagnesium chloride (0.51 mL, 2.0 M in THF) in 1 portion.The reaction temperature was brought to 40° C. and then succinicanhydride (55.0 mg, 0.55 mmol) was added in 1 portion. After aging for45 min, analysis by HPLC of the reaction mixture indicated 50% probucolmonosuccinate, 7% probucol disuccinate, and 43% probucol.

Example 30

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 20 mL anhydrous tetrahydrofuran (THF). To theresulting solution was slowly added benzylmagnesium chloride (10.08 mL,2.0 M in THF) over 2 min. Once addition was complete the reactiontemperature was brought to 40° C. and then succinic anhydride (1.1 g,10.99 mmol) was added in 1 portion. After aging for 15 min, analysis byHPLC of the reaction mixture indicated 58% probucol monosuccinate, 10%probucol disuccinate, and 32% probucol.

Example 31

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 20 mL anhydrous tetrahydrofuran (THF). To theresulting solution was slowly added octylmagnesium chloride (10.06 mL,2.0 M in THF) over 2 min. Once addition was complete the reactiontemperature was brought to 40° C. and then succinic anhydride (1.1 g,10.99 mmol) was added in 1 portion. After slowly quenching the reactionwith 1 N HCl and diluting with EtOAc, the biphasic reaction was cooledto room temperature and the phases were separated. Analysis by HPLC ofthe reaction mixture indicated 53% probucol monosuccinate, 8% probucoldisuccinate, and 39% probucol.

Example 32

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 20 mL anhydrous THF. To the resulting solutionwas slowly added benzylmagnesium chloride (9.91 mL, 2.0 M in THF) atsuch a rate to maintain the internal reaction temperature between 40-50°C. Once addition was complete the reaction temperature was brought to40° C. and then succinic anhydride (1.03 g, 10.29 mmol) was added in 1portion. After aging for 15 min, analysis by HPLC of the reactionmixture indicated 56% probucol monosuccinate, 9% probucol disuccinate,and 35% probucol.

Example 33

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 10 mL anhydrous THF. To the resulting solutionwas slowly added benzylmagnesium chloride (9.88 mL, 2.0 M in THF) atsuch a rate to maintain the internal reaction temperature between 40-50°C. Once addition was complete the reaction temperature was brought to40° C. and then succinic anhydride (0.965 g, 9.64 mmol) was added as aTHF (10 mL) solution over 45 min. After aging for 45 min, analysis byHPLC of the reaction mixture indicated 58% probucol monosuccinate, 8%probucol disuccinate, and 34% probucol.

Example 34

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 20 mL anhydrous THF. To the resulting solutionwas slowly added benzylmagnesium chloride (10.8 mL, 2.0 M in THF) atsuch a rate to maintain the internal reaction temperature between 40-50°C. Once addition was complete the reaction temperature was brought to40° C. and then succinic anhydride (1.03 g, 10.29 mmol) was added in 1portion. After aging 45 min, analysis by HPLC of the reaction mixtureindicated 52% probucol monosuccinate, 6% probucol disuccinate, and 42%probucol.

Example 35

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 20 mL anhydrous THF. To the resulting solutionwas slowly added benzylmagnesium chloride (8.9 mL, 2.0 M in THF) at sucha rate to maintain the internal reaction temperature between 40-50° C.Once addition was complete the reaction temperature was brought to 40°C. and then succinic anhydride (1.03 g, 10.29 mmol) was added in 1portion. After aging 45 min, analysis by HPLC of the reaction mixtureindicated 56% probucol monosuccinate, 11% probucol disuccinate, and 33%probucol.

Example 36

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 20 mL anhydrous THF. To the resulting solutionwas slowly added benzylmagnesium chloride (8.2 mL, 2.0 M in THF) at sucha rate to maintain the internal reaction temperature between 40-50° C.Once addition was complete the reaction temperature was brought to 40°C. and then succinic anhydride (1.03 g, 10.29 mmol) was added in 1portion. After aging 40 min, analysis by HPLC of the reaction mixtureindicated 52% probucol monosuccinate, 11% probucol disuccinate, and 37%probucol.

Example 37

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 20 mL anhydrous THF. To the resulting solutionwas slowly added benzylmagnesium chloride (7.5 mL, 2.0 M in THF) at sucha rate to maintain the internal reaction temperature between 40-50° C.Once addition was complete the reaction temperature was brought to 40°C. and then succinic anhydride (1.03 g, 10.29 mmol) was added in 1portion. After aging 40 min, analysis by HPLC of the reaction mixtureindicated 48% probucol monosuccinate, 10% probucol disuccinate, and 42%probucol.

Example 38

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 10 mL anhydrous THF. To the resulting solutionwas slowly added benzylmagnesium chloride (9.86 mL, 2.0 M in THF) atsuch a rate to maintain the internal reaction temperature between 40-50°C. Once addition was complete the reaction temperature was brought to40° C. and then succinic anhydride (1.03 g, 10.28 mmol) in THF (10.2 mL)was added over 30 min. After slowly quenching the reaction with 4 N HCl,the biphasic reaction was cooled to room temperature and the phases wereseparated. Analysis by HPLC of the organic layer at this point indicated64% probucol monosuccinate, 13% probucol disuccinate, and 23% probucol.

Example 39

In a dry 50 mL 3-neck round bottom fitted with a reflux condenser,nitrogen inlet, thermocouple and stir bar was charged probucol (5.0 g,9.67 mmol) followed by 10 mL anhydrous tetrahydrofuran (THF). To theresulting solution was slowly added benzylmagnesium chloride (9.86 mL,2.0 M in THF) at such a rate to maintain the internal reactiontemperature between 40-50° C. Once addition was complete the reactiontemperature was brought to 40° C. and then succinic anhydride (1.03 g,10.28 mmol) in THF (10.2 mL) was added over 30 min. Analysis by HPLC ofthe reaction mixture indicated 64% probucol monosuccinate, 13% probucoldisuccinate, and 23% probucol. After slowly quenching the reaction with4 N HCl, the biphasic reaction was cooled to room temperature and thephases were separated. The organic cut was diluted with THF and waterand then the phases were separated again.

After washing the THF cut with 5 N NaOH, the THF solution wasazeotropically dried under reduced pressure at 45° C. with the additionof dry THF. Following a solvent switch to heptane, the resulting slurrywas cooled to 0° C. with stirring and vacuum filtered. The residue iswashed with cold heptane and to the wet cake is added tert-butylmethylether (MTBE) with stirring. The resulting slurry was filtered and theresidue washed with fresh MTBE. The MTBE filtrates were then combinedand washed sequentially with 1 N HCl and water. The organic cut was thensolvent switched to heptane at 70° C. under reduced pressure. Theheptane solution was cooled to 5° C. over 45 min and the resultingslurry was filtered, washed with cold heptane and dried to yield 3.42 gMSP (57.3% yield, 97 LCAP) as a white solid, m.p. 139-142° C. ¹H-NMR(300 MHz, CDCl₃): 7.62 (s, 2H), 7.45 (s, 2H), 5.37 (s, 1H), 3.00 (t, 2H,J=6.8 Hz), 2.78 (t, 2H, J=6.8 Hz), 1.46 (s, 6H), 1.44 (s, 18H), 1.34 (s,18H).

Example 40

In a dry 10 mL round bottom fitted with nitrogen inlet, thermocouple andstir bar was charged probucol (1.0 g, 1.93 mmol) followed by 4 mLanhydrous THF. To the resulting solution was slowly added n-butyllithium (1.58 mL, 2.5 M in hexanes) at such a rate to maintain theinternal reaction temperature between 40-52° C. Once addition wascomplete additional THF (2 mL) was added and the reaction temperaturewas brought to 40° C. Solid succinic anhydride (0.20 g, 2.00 mmol) wasadded to the resulting solution in 1 portion. After aging for 15 min,analysis by HPLC of the reaction mixture indicated 15% probucolmonosuccinate, 4% probucol disuccinate, and 81% probucol.

Example 41

In a dry 10 mL round bottom fitted with nitrogen inlet, thermocouple andstir bar was charged probucol (1.0 g, 1.93 mmol) followed by 4 mLanhydrous THF. To the resulting solution was slowly added hexyl lithium(1.70 mL, 2.3 M in hexanes) at such a rate to maintain the internalreaction temperature between 40-50° C. Once addition was completeadditional THF (2 mL) was added and the reaction temperature was broughtto 40° C. Solid succinic anhydride (0.20 g, 2.00 mmol) was added to theresulting solution in 1 portion. After aging for 15 min, analysis byHPLC of the reaction mixture indicated 20% probucol monosuccinate, 5%probucol disuccinate, and 75% probucol.

Example 42

In a dry 10 mL round bottom fitted with nitrogen inlet, thermocouple andstir bar was charged probucol (1.0 g, 1.93 mmol) followed by 4 mLanhydrous THF. To the resulting solution was slowly added hexyl lithium(1.70 mL, 2.3 M in hexanes) at such a rate to maintain the internalreaction temperature between 40-50° C. Once addition was complete DMF (2mL) was added and the reaction temperature was brought to 40° C. Solidsuccinic anhydride (0.20 g, 2.00 mmol) was added to the resultingsolution in 1 portion. After aging for 15 min, analysis by HPLC of thereaction mixture indicated 18% probucol monosuccinate, 1% probucoldisuccinate, and 81% probucol.

Example 43

In a dry 10 mL round bottom fitted with nitrogen inlet, thermocouple andstir bar was charged probucol (1.0 g, 1.93 mmol) followed by 2 mLanhydrous THF. To the resulting solution was slowly addedbenzylmagnesium chloride (1.97 mL, 2.0 M in THF) at such a rate tomaintain the internal reaction temperature between 40-50° C. Onceaddition was complete DMF (4 mL) was added and the reaction was aged atroom temperature. Iodo-acetic acid ethyl ester (0.24 mL, 2.03 mmol) wasadded to the resulting solution in 1 portion. The reaction was heated to60° C. and aged overnight. Analysis by HPLC of the reaction mixtureindicated ca. 70% probucol and 30% probucol-acetic acid ethyl ester (aprobucol monoether) of the following formula

Example 44

In a dry 10 mL round bottom fitted with nitrogen inlet, thermocouple andstir bar was charged probucol (1.0 g, 1.93 mmol) followed by 2 mLanhydrous THF. To the resulting solution was slowly addedbenzylmagnesium chloride (1.97 mL, 2.0 M in THF) at such a rate tomaintain the internal reaction temperature between 40-50° C. Onceaddition was complete DMF (4 mL) was added followed by sodiumiodoacetate (0.44 g, 2.12 mmol) and the resulting solution was heated to60° C. and aged overnight. Analysis by HPLC of the reaction mixturefollowing an acid quench indicated ca. 98% probucol and 2%probucol-acetic acid (a probucol monoether) of Formula XVI

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A process of manufacturing a compound of Formula I or salts thereof

wherein R¹, R², R³, and R⁴ are independently selected from the groupconsisting of hydrogen and alkyl, said alkyl optionally substituted byhydroxy, alkyl, alkenyl, acyl, nitro, amino, halo, carboxy and cyano; R⁵and R⁶ are the same or different and independently selected from thegroup consisting of alkyl, alkenyl, and aryl all of which can beoptionally substituted by hydroxy, alkyl, alkenyl, acyl, nitro, amino,halo, carboxy and cyano; R⁵ and R⁶ can come together to form acarbocyclic ring; X is selected from the group consisting of hydrogen,an optionally substituted unsaturated acyl having from 1 to 18 carbonatoms, and an optionally substituted saturated acyl having from 1 to 18carbon atoms, said optionally substituted unsaturated acyl andoptionally substituted saturated acyl optionally containing a polar orcharged functionality; Y is selected from the group consisting of anoptionally substituted unsaturated acyl having from 1 to 18 carbon atomsand an optionally substituted saturated acyl having from 1 to 18 carbonatoms, said optionally substituted unsaturated acyl and optionallysubstituted saturated acyl optionally containing a polar or chargedfunctionality; comprising: reacting a compound of Formula II

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined, with anarylalkylmagnesium halide in the presence of a solvent, co-solvent orsolubilizing reagent or mixtures thereof to form a magnesium salt;reacting said magnesium salt with a compound selected from the groupconsisting of a saturated or unsaturated acyl halide, saturated orunsaturated carboxylic acid anhydride and a saturated or unsaturatedactivated carboxylic acid ester, all of which may optionally besubstituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, amino,halo, protected carboxy and cyano; separating and isolating saidcompound of Formula I.
 2. The process of claim 1, wherein R¹, R², R³,and R⁴ are independently alkyl, said alkyl optionally substituted byhydroxy, alkyl, alkenyl, acyl, nitro, amino, halo, carboxy and cyano; R⁵and R⁶ are alkyl which can be optionally substituted by hydroxy, alkyl,alkenyl, acyl, nitro, amino, halo, carboxy and cyano; X is H; Y isselected from the group consisting of an optionally substitutedunsaturated acyl having from 1 to 18 carbon atoms and an optionallysubstituted saturated acyl having from 1 to 18 carbon atoms, saidoptionally substituted unsaturated acyl and optionally substitutedsaturated acyl optionally containing a polar or charged functionality.3. The process of claim 2, wherein R¹, R², R³, and R⁴ are t-butyl; R⁵and R⁶ are methyl; X is H; Y is selected from the group consisting of anoptionally substituted unsaturated acyl having from 1 to 18 carbon atomsand an optionally substituted saturated acyl having from 1 to 18 carbonatoms, said optionally substituted unsaturated acyl and optionallysubstituted saturated acyl optionally containing a polar or chargedfunctionality.
 4. The process of claims 1, 2 or 3, wherein thearylalkylmagnesium halide is benzylmagnesium chloride.
 5. The process ofclaim 1, wherein the solvent comprises THF, toluene or a mixturethereof.
 6. The process of claim 5, wherein the solvent comprises THF.7. The process of claim 1, wherein the magnesium salt is reacted with asaturated or unsaturated acyl halide.
 8. The process of claim 1, whereinthe magnesium salt is reacted with a saturated or unsaturated carboxylicacid anhydride.
 9. The process of claim 8, wherein the saturated orunsaturated carboxylic acid anhydride is succinic anhydride.
 10. Theprocess of claim 1, wherein the magnesium salt is reacted with asaturated or unsaturated activated carboxylic acid ester.
 11. A processof manufacturing a compound of Formula V or salts thereof

comprising: reacting a compound of Formula IV

with an arylalkylmagnesium halide in the presence of a solvent,co-solvent or solubilizing reagent or mixtures thereof to form amagnesium salt; reacting said magnesium salt with a compound selectedfrom the group consisting of a saturated or unsaturated acyl halide,saturated or unsaturated carboxylic acid anhydride and a saturated orunsaturated activated carboxylic acid ester, all of which may optionallybe substituted by one or more selected from the group consisting ofprotected hydroxy, alkyl, alkenyl, acyl, nitro, protected amino, amino,halo, protected carboxy and cyano; separating and isolating saidcompound of Formula V.
 12. The process of claim 11, wherein thearylalkylmagnesium halide is benzylmagnesium chloride.
 13. The processof claim 12, wherein the solvent comprises THF, toluene or a mixturethereof.
 14. The process of claim 13, wherein the solvent comprises THF.15. The process of claim 14, wherein the magnesium salt is reacted witha saturated or unsaturated acyl halide.
 16. The process of claim 14,wherein the magnesium salt is reacted with succinic anhydride.
 17. Theprocess of claim 14, wherein the magnesium salt is reacted with asaturated or unsaturated activated carboxylic acid ester.